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Kainate Receptors in Health and Disease

Juan Lerma1,* and Joana M. Marques1 1Instituto de Neurociencias, CSIC-UMH, San Juan de Alicante, 03550 Spain *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2013.09.045

Our understanding of the molecular properties of kainate receptors and their involvement in synaptic phys- iology has progressed significantly over the last 30 years. A plethora of studies indicate that kainate receptors are important mediators of the pre- and postsynaptic actions of glutamate, although the mechanisms under- lying such effects are still often a topic for discussion. Three clear fields related to their behavior have emerged: there are a number of interacting proteins that pace the properties of kainate receptors; their activity is unconventional since they can also signal through G proteins, behaving like metabotropic recep- tors; they seem to be linked to some devastating brain diseases. Despite the significant progress in their importance in brain function, kainate receptors remain somewhat puzzling. Here we examine discoveries linking these receptors to physiology and their probable implications in disease, in particular mood disorders, and propose some ideas to obtain a deeper understanding of these intriguing proteins.

A Historical Overview The absence of specific antibodies against different KAR Most excitatory synapses in the brain use the amino acid gluta- subunits has been a significant limitation in terms of exploring re- mate as a neurotransmitter. Since the excitatory properties of ceptor distribution. Thus, most of the information regarding their glutamate were postulated nearly 40 years ago, an extraordinary tissue expression comes from in situ hybridization studies that, wealth of data has accumulated on the types of synaptic re- although informative, cannot reveal the subcellular distribution sponses triggered by this neurotransmitter. Glutamate acts on of a given subunit. Relatively good and specific antisera against a variety of receptor proteins, initially classified by the mecha- the KAR subunits GluK2/3 and GluK5 are now available, nisms that they use to transmit signals (i.e., metabotropic versus although not all work properly in immunocytochemistry. Never- ionotropic). A more precise specification of ionotropic receptors theless, some general rules could be extracted from all these into three types was subsequently proposed, based on the studies. GluK2 subunits are mostly expressed by principal cells agonist that activates or binds to them. Thus, AMPA, kainate, (hippocampal pyramidal cells; both hippocampal and cerebellar and NMDA receptors (AMPARs, KARs, and NMDARs, respec- granule cells; cortical pyramidal cells), while GluK1 is mainly pre- tively) are recognized as the main effectors of glutamate at syn- sent in hippocampal and cortical interneurons (Paternain et al., apses. We now know that this classification is misleading, since 2003) as well as in Purkinje cells and sensory neurons. GluK3 there is certain cross-reactivity between agonists and receptors is poorly expressed, appearing in layer IV of the neocortex and and only recently have some new compounds enriched the phar- dentate gyrus in the hippocampus (Wisden and Seeburg, macological armamentarium (see Jane et al., 2009 for a review). 1993). GluK4 is mainly expressed in CA3 pyramidal neurons, Unlike other receptors, studies of KARs suffered from the lack dentate gyrus, neocortex, and Purkinje cells, while GluK5 is ex- of specific compounds to activate or block these proteins. First pressed abundantly in the brain (Bahn et al., 1994). of all, kainate is derived from the seaweed known as ‘‘kaininso’’ The functional description of KARs within the CNS (Lerma in Japanese, and it is a mixed agonist that can also activate et al., 1993) and the molecular identification of KAR subunits rep- AMPARs. This fact led to certain misinterpretations of the role resented real breakthroughs in the study of these receptors, as of KARs in the brain and, even nowadays, some related errors did the discovery that GYKI53655, a 2,3, benzodiazepine, was can be detected in the literature. In addition, the prototypical essentially inactive at KARs (Paternain et al., 1995; Wilding and AMPAR agonist, AMPA, can also activate diverse KARs. Like Huettner, 1995) (with the exception of a few particular assem- the AMPARs and NMDARs, KARs are tetrameric combinations blies on which it may act at high concentrations; see Perrais of a number of subunits: named GluK1, GluK2, GluK3, GluK4, et al., 2009), and constitute the foundation upon which our and GluK5 (previously known as GluR5–GluR7 and KA1 and understanding of KARs has been constructed. KA2, respectively). Of these, GluK1–GluK3 may form functional On the basis of the data collected over the last 30 years of homomeric or heteromeric receptors, while GluK4 and GluK5 research, how do we now envisage the physiological role of only participate in functional receptors when partnering any of KARs? A comprehensive analysis of the profuse yet often the GluK1–GluK3 subunits. The structural repertoire of KAR sub- controversial literature on KARs leads us to conclude that these types is further extended by editing of the GluK1 and GluK2 receptors play significant roles in the brain at three main levels. In receptor subunit pre-mRNAs at the so-called Q/R site of the sec- the first place, they mediate postsynaptic depolarization and ond membrane domain. More isoforms also arise from the alter- they are responsible for carrying some of the synaptic current, native splicing of GluK1–GluK3 subunits, while GluK4 and GluK5 although this only happens at some synapses. Second, KARs seem not to be subjected to this type of processing. can modulate the synaptic release of neurotransmitters such

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Table 1. The Kainate Receptor Interactome Interactor KAR Subunit Direct Role References Actinfilin GluK2 Yes Receptor degradation through ubiquitination Salinas et al., 2006 b-catenin GluK2 No Plasma membrane dynamics Coussen et al., 2005 Cadherin GluK2 ND Receptor trafficking/subcellular localization Coussen et al., 2005 Calcineurin GluK2 Yes Ca2+-regulation of channel function Coussen et al., 2005 Calmodulin GluK2 Yes ND Coussen et al., 2005 Contactin GluK2 Yes ND Coussen et al., 2005 COPI GluK5 Yes Receptor trafficking Vivithanaporn et al., 2006 Dynamin-1 GluK2 Yes ND Coussen et al., 2005 Dynamitin GluK2 Yes ND Coussen et al., 2005 14.3.3 GluK1, GluK2, GluK5 Yes Receptor trafficking Coussen et al., 2005; Vivithanaporn et al., 2006 4.1N GluK1, GluK2 Yes Receptor trafficking Copits and Swanson, 2013b GRIP GluK2, K5 Yes Receptor trafficking Hirbec et al., 2003 KRIP6 GluK2 Yes Receptor gating Laezza et al., 2007 NETO1 GluK1-3 Yes Ion channel function Zhang et al., 2009; Copits et al., 2011; Straub et al., 2011a; Tang et al., 2011 NETO2 GluK1-3 Yes Ion channel function Zhang et al., 2009; Copits et al., 2011 NSF GluK2 Yes ND Coussen et al., 2005 PICK1 GluK2, GluK5 Yes Receptor trafficking Hirbec et al., 2003 Profillin II GluK2 Yes Receptor trafficking Coussen et al., 2005; Mondin et al., 2010 PSD95 GluK2, GluK5 Yes Alters receptor function by reducing Garcia et al., 1998 desensitization SAP102 GluK2, GluK5 Yes Receptor clustering; Garcia et al., 1998 SAP90 GluK2, GluK5 Yes Receptor clustering; modulation of Garcia et al., 1998 desensitization SAP97 GluK2 Yes Receptor clustering Garcia et al., 1998 SNAP25 GluK5 ND Receptor trafficking Selak et al., 2009 Spectrin GluK2 Yes ND Coussen et al., 2005 Syntenin GluK1, GluK2 Yes Plasma membrane dynamics Hirbec et al., 2003 VILIP-1 GluK2 Yes ND Coussen et al., 2005 VILIP-3 GluK2 Yes ND Coussen et al., 2005 ND, not determined.

as GABA and glutamate at different sites. Third, they play an tion and the wealth of new data available implicating KARs in influential role in the maturation of neural circuits during develop- brain pathology. ment. These roles are frequently fulfilled in an unconventional way given that KARs can signal by activating a G protein, The Explosion of KAR Interacting Proteins behaving more like a metabotropic receptor than an ion channel. To date, and like many other receptors and channels, a whole set This noncanonical signaling is totally unexpected considering of proteins have been identified that can interact with KAR sub- that the three iGluRs share a common molecular design, as units (Table 1). Indeed, the identification of these proteins has recently revealed by their crystal structure (Mayer, 2005; Furu- changed our view on how KARs function and provided insight kawa et al., 2005; Gouaux, 2004). into the discrepancies between native and recombinant KAR It is difficult to do justice to the literature generated on KARs properties. While the exact role of these interactions still remains over the years in the short space available, and indeed, there to be unambiguously established, the role of KARs in physiology are several reviews that have described many of the molecular, will be difficult to understand without taking into account the biophysical, pharmacological, and functional aspects of these contribution of these proteins. For instance, KARs and many of receptors (Rodrigues and Lerma, 2012; Contractor et al., 2011; these proteins seem to undergo transient interactions that pro- Lerma et al., 2001, Lerma, 2003, 2006; Copits and Swanson, mote receptor trafficking, regulating their surface expression. 2012; Vincent and Mulle, 2009; Coussen and Mulle, 2006; Pin- PDZ motif-containing proteins such as postsynaptic density pro- heiro and Mulle, 2006; Tomita and Castillo, 2012; Jaskolski tein 95 (PSD-95), protein interacting with C kinase-1 (PICK1), and et al., 2005; Matute, 2011). Hence, in this Review we will focus glutamate receptor interacting protein (GRIP) seem to be rele- primarily on the data that have influenced our notion of KAR func- vant for the stabilization of KARs at the synaptic membrane

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(Hirbec et al., 2003). However, PDZ-binding motifs in the C termi- A number of studies have identified trafficking and targeting nus of KAR subunits are also present in other glutamate recep- motifs in KAR subunits and increased our knowledge of the tors. Thus, these interacting proteins are not selective for mechanisms controlling KAR targeting and surface expression KARs. Although interactions with PDZ domains cannot entirely (see reviews by Pinheiro and Mulle, 2006 and Contractor et al., account for the subcellular distribution of KARs, the interaction 2011). However, many other aspects of KAR biology still remain with PDZ proteins produce apparently different outcomes for to be defined. For instance, many of the mechanisms supporting these receptors, as these proteins prevent AMPAR internaliza- the polarized targeting of KARs to different neuronal populations tion but facilitate KAR internalization (Hirbec et al., 2003). are unknown. It was recently demonstrated that the SNARE protein SNAP- Recently, two integral membrane proteins have been identi- 25 is a KAR-interacting protein (Selak et al., 2009). In MF-CA3 fied that seem to be true auxiliary subunits of KARs (Zhang synapses, activity-dependent stimulation of PKC intensifies et al., 2009; Straub et al., 2011a; Tang et al., 2011). Neuropilin this interaction and triggers the internalization of KARs, leading Tolloid-like 1 and Neuropilin Tolloid-like 2 (Neto1 and Neto2) to a specific long-term depression (LTD) of KAR-mediated are auxiliary proteins of native KARs that exert an important influ- synaptic transmission. Interestingly, these results implied that ence on their function. Indeed, these proteins radically alter the SNAP25, classically regarded as a member of the exocytotic gating properties of KARs, accounting for a number of previously machinery, may be also involved in endocytosis (Selak et al., unexplained properties of these receptors (see Copits and 2009). This view has been recently supported by a report Swanson, 2012; Lerma, 2011; Tomita and Castillo, 2012 for defining a role for SNAP25 in clathrin-dependent endocytosis recent reviews). Neto1 and Neto2 share an identical and unique at conventional synapses (Zhang et al., 2013). KARs at these domain structure, representing a novel subfamily of transmem- synapses may also contain GluK2 subunits and, recently, it brane proteins containing CUB and LDLa domains. Neto1 was was proposed that this mechanism of LTD requires the synergis- first identified as a protein that interacts with the NMDA receptor tic SUMOylation of GluK2 subunits, initiated by PKC phosphor- (Ng et al., 2009), although a number of studies then illustrated ylation (Chamberlain et al., 2012). This new mechanism expands that it has a more striking influence on the function of KARs. In the repertoire of events associated with synaptic plasticity. general, the coexpression of Neto1 and Neto2 with KARs in The possibility of modifying information transfer at this level recombinant systems alters the gating properties of the latter. has been further illustrated by the recent observation that The most obvious effect is that the onset of the desensitization CaMKII-mediated phosphorylation of GluK5 subunits also de- of kainate-evoked responses decelerates (Copits et al., 2011; presses a KAR-mediated synaptic component at CA3 synapses Straub et al., 2011b; Fisher and Mott, 2013), while recovery (Carta et al., 2013). A spike timing-dependent plasticity protocol, from the desensitized state accelerates. This modulation implies known to activate CaMKII in a number of synapses and induce that the kainate-induced steady current persists for longer AMPAR LTP, induces phosphorylation of GluK5-containing periods in the presence of an agonist (e.g., Fisher and Mott, receptors in MF-CA3 synapses, resulting in LTD of the KAR- 2013). This effect is evident for all subunits and reconciles the mediated synaptic component. Rather than involving endocy- properties of recombinant receptors with the reported action of tosis of KARs, this depression is evoked by the lateral diffusion kainate in more physiological preparations, where it behaves of these receptors upon uncoupling of the PSD-95 scaffolding as a strong depolarizing agent. Moreover, the rapid deactivation protein at the postsynaptic density (Carta et al., 2013; see also of kainate-induced currents upon agonist removal is also decel- Copits and Swanson, 2013a). erated in the presence of Neto, suggesting an increase in the Additional proteins that interact and directly modulate the steady-state affinity of KARs when associated to Neto. Indeed, properties of KARs have also been identified. These include pro- equilibrium agonist affinity substantially increased in the pres- teins such as kainate receptor interacting protein for GluR6 ence of Neto, again reconciling the properties of recombinant (KRIP6; Laezza et al., 2007), a protein that belongs to the BTB/ and native KARs. kelch family and that binds to a C-terminal motif distinct to the A prominent feature of KAR-mediated excitatory postsynaptic

PDZ binding motif. Coexpression of KRIP6 with GluK2 reduces currents (EPSCKARs) is that they are characteristically slower and both the peak current and steady-state desensitization in recom- smaller than AMPAR-mediated EPSCs (Castillo et al., 1997; binant systems, as well as that of native KARs. Interestingly, Vignes et al., 1998; Frerking et al., 1998). This cannot be antici- KRIP6 does not affect the surface expression of GluK2 recep- pated from the properties of recombinant receptors, since single tors, indicating that the interaction with this protein only affects KARs and AMPARs have similar affinity and activation-inactiva- channel gating. Another BTB/kelch family member, actinfilin, is tion kinetics (see Lerma, 1997). A prominent perisynaptic locali- also thought to interact with GluK2 subunits (Salinas et al., zation of KARs was also ruled out (Castillo et al., 1997) and if both 2006), this protein promoting the degradation of GluK2 receptors receptor subtypes colocalize at the synapse, one would expect by acting as a scaffold to link this subunit to the E3 ubiquitin- similar kinetics for the KAR- and AMPAR-mediated synaptic re- ligase complex. In this way, actinfilin regulates the synaptic sponses. Although the subunit composition of KARs may have expression of receptors containing GluK2 (Salinas et al., 2006), an influence in EPSC kinetics (Contractor et al., 2001; Barberis although more work will be necessary to reveal what is the phys- et al., 2008; Fernandes et al., 2009), no convincing explanation iological impact of these BTB/kelch proteins. For instance, it is for this discrepancy had been available until the discovery that known that KRIP6 can interact with PICK1, forming clusters Neto proteins confer higher agonist affinity to KARs and impose that lack GluK2 and preventing the mutual regulation of GluK2 significantly slower deactivation kinetics. Curiously, the kinetics containing KARs (Laezza et al., 2008). of KARs imposed by Neto protein is remarkably similar to those

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A B -60 mV; No drugs -70 mV; GYKI53655 Figure 1. Kinetic Similarities between NMDAR MF->CA3 and KARs KAR (A) NMDARs, AMPARs, and KARs coexist in Mossy NMDAR Fiber to CA3 neuron synapses. -30 mV; CNQX (B) Synaptic responses mediated by AMPAR are AMPAR much faster than the KAR and NMDAR components, as can be seen after their pharmacological isolation. 100 (C) Responses mediated by AMPARs, NMDARs, and 50 ms pA KARs are superimposed once scaled. Note how C Scaled responses D KARs and NMDARs generate responses with a remarkable similar onset and decay time courses. (D) The slow time course of KARs is accounted for by their interaction with Neto proteins. Note how

EPSCAMPAR KAR-mediated EPSCs are accelerated in the Neto1 KO mice, approaching the characteristics of the NETO1 KO EPSCNMDAR AMPAR-mediated component (records reproduced with permission from Straub et al., 2011a). EPSCKAR 100 ms WT (E) Participation of postsynaptic KARs to MF-CA3 synaptic transmission: averaged traces illustrate the E F effect of KARs antagonist UBP310 on the depola- -Ctrl -UBP310 wild-type GluK2-/- rizing envelope (shaded area) induced by a train of stimuli. KARs blockade reduces summation and prevents neuron firing (spikes are shown truncated) (from Pinheiro et al., 2013). (F) CA3 pyramidal cell firing in response to a physi- ological granule cell firing pattern of stimulation (ex- 10 0 5 10 15 20 25 30 0 5 10 15 20 25 30 tracted from an in vivo recording of a freely moving 0.5 s mV s s mouse) in WT and a GluK2-deficient mouse, revealing the contribution of postsynaptic KARs to neuronal output (from Sachidhanandam et al., 2009). of NMDARs (see Figure 1). The difference between NMDAR acti- GluK2 in synaptic contacts, despite the fact that synaptic vation kinetics and that of the faster AMPARs provides adequate KARs are normally associated with Netos in hippocampal timing for activation, since the Mg2+ blockade implies that slices. Indeed, KAR-mediated EPSCs in brain slices display

NMDAR activation would not be operative until sufficient mem- distinct kinetics in Neto-deficient animals and EPSCKARs are brane depolarization is attained. In contrast, the functional signif- present in mice even deficient for the two Neto proteins, yet icance of the slower kinetics of KARs is starting to be illustrated with fast kinetics, consistent with the idea that Netos are not by examples that provide comprehensive roles for such a key elements in the targeting of KARs to the synapse (Tang prolonged current in synaptic integration (Frerking and Ohliger- et al., 2011). Frerking, 2002; Goldin et al., 2007; Sachidhanandam et al., From these data, it is clear that Netos exert an important influ- 2009; Pinheiro et al., 2013; see Figure 1). ence on KARs, which may vary depending on the subunit com- Another striking action of Neto1 and Neto2 is that association bination. However, Neto proteins are not specific to KARs. with these proteins greatly reduces inward rectification of KAR- Indeed, Neto1 was initially identified as a NMDAR interactor. mediated currents without modifying Ca2+ permeability (Fisher While Neto2 was originally thought to partner KARs only, it was and Mott, 2012). It seems that three positive charges (RKK) in recently reported to also interact with distant proteins, such as the C-terminal of Neto proteins preclude internal polyamine the neuron-specific K+-Cl cotransporter KCC2, which is essen- blockade of KAR channel. This effect is reminiscent of stargazin tial to maintain Cl homeostasis in neurons (Ivakine et al., 2013). in AMPARs (Soto et al., 2007). However, the functional implica- These data raise the possibility that Neto proteins play a more tion of this action remains to be defined. wide-ranging role than initially anticipated. Nevertheless, the Apart from the clear effect of Netos on KAR channel gating interesting question that remains to be answered is whether and on current amplitudes (see Copits and Swanson, 2012), it the association of Neto1/2 with KARs could be regulated by remains unclear whether Neto proteins are involved in KAR physiological signals, and under what circumstances this targeting to the synapse, although there is weak evidence indi- occurs. Since KARs are fully operational in the absence of cating that this may be possible. Cultured hippocampal neurons Neto, it is possible that two populations of KARs might exist, express native KARs, but these are not targeted to synapses those with and without Neto probably fulfilling complementary (Lerma et al., 1997). However, a small proportion of ESPCs functional roles. may be mediated by KARs when such cells are transfected Recently, the group of Maricq has identified in the worm with Neto2 and GluK1, indicating that exogenous Neto2 may C. elegans SOL-2, a CUB-domain protein that associates with target a small proportion of exogenous GluK1 to synapses both the related auxiliary subunit SOL-1 and with the GLR-1 (Copits et al., 2011). Similar effects were observed in cerebellar AMPAR (Wang et al., 2012). Like Neto1, SOL-2 contributes to granule cells and with GluK2 (Zhang et al., 2009). However, the kinetics of receptor desensitization and is an essential although GluK2 association with PSD95 is reduced in component of AMPAR complexes at worm synapses. These Neto2 null mice (Tang et al., 2012), the lack of Neto2 expres- data indicate that several different interacting proteins could sion does not prevent the presence of endogenous GluK1 or form the receptor complex at synapses.

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Figure 2. Kainate Receptors Signal through Two Different and Independent Pathways On the one hand, the gating of the channel (canonical pathway, a) is responsible for mem- brane depolarization and the synaptic responses (b) and probably for the facilitation of neurotrans- mitter release at some synapses. These receptors bear ancillary proteins, like Neto. On the other hand, KARs activate G proteins (c), signaling through the stimulation of phospholipase C and PKC in a manner independent of ion flux. It is unknown whether these receptors are coupled to Neto proteins and whether they require an inter- mediate protein to couple to G protein. The main effects so far documented are: the increase in neuronal excitability through the inhibition of afterhypopolarizing current (IAHP, d), leading to an increase in the firing frequency of these neurons (e); the facilitation and inhibition of transmitter release, probably through the modulation of cal- 2+ cium currents (ICa , f); and their role in the matu- ration of neuronal circuits during development.

an unconventional metabotropic mecha- nism involving G proteins and second messengers at inhibitory CA1 hippocam- pal synapses (Rodrı´guez-Moreno et al., 1997; Clarke et al., 1997). This signaling follows presynaptic inhibition of GABA release and is dependent on G protein activation and PKC activity (Rodrı´guez- The Uniqueness of Ion-Dependent KAR Gating Moreno and Lerma, 1998; Rodrı´guez-Moreno et al., 2000). Later, One unique feature of KARs is that their channel gating requires this nonconventional mode of signaling was compellingly estab- external monovalent cations and anions. This ion-dependent lished in dorsal root ganglion neurons and was shown to be channel gating differentiates KARs from other ligand-gated independent of ion flux (Rozas et al., 2003). Since then, an channels, including the closely related NMDARs and AMPARs increasing number of metabotropic actions triggered by KARs (Paternain et al., 2003; Bowie, 2002; see Bowie, 2010 for a have been described in many cell types and in different regions review). Indeed, crystallographic studies have revealed the exis- of the CNS, particularly in association with the presynaptic con- tence of an ion binding pocket in KAR subunits (Plested and trol of neurotransmitter release or the postsynaptic regulation of Mayer, 2007; Plested et al., 2008). The absolute requirement of neuronal excitability (see Rodrigues and Lerma, 2012 for a recent ion binding for channel opening indicates that KAR activity review and Figure 2). However, key aspects of the molecular would be abolished if this binding site remained unoccupied, mechanisms underlying this noncanonical signaling still remain prompting the suggestion that this site might be used as a target unclear, including how KARs activate G proteins to trigger these for specific allosteric modulation of KARs by external agents. effects and what determines the mode of action of KARs The question as to what might be the physiological role of (i.e., conventional ionotropic versus noncanonical metabotropic such a strict dependence of the channel gate has not been signaling). answered yet but prompted some possibilities. For instance, The evidence for a direct interaction between KARs and G under intense neuronal activity, a situation under which external proteins is limited. Prior to describing the metabotropic behavior Na+ levels drop, activation of KARs would be limited, constituting of KARs, the Pertussis toxin (PTx)-sensitive binding of an agonist a brake for tissue damage. Indeed, a large fraction of KARs to goldfish-purified KARs was demonstrated biochemically, seems to have unoccupied the cation binding site at physiolog- providing a link between KARs and PTx-sensitive proteins (Zie- ical salt concentrations, making them insensitive to activation by gra et al., 1992). While similar PTx-sensitive KAR agonist-binding released glutamate (Plested et al., 2008). Much work remains to was also observed in hippocampal membranes (Cunha et al., be done to figure out whether this fraction of incompetent KARs 1999), this kind of interaction does not seem to be that related could be modulated up and down as a way to regulate the weight to the functional signal transduced by KAR activation through of these receptors in, for instance, synaptic transmission. G protein activity. It is expected that undergoing proteomic anal- ysis of KAR subunits identify partners that could account for the A Receptor with Two Modes of Signaling coupling between an ion channel receptor and a G protein. High-resolution structural analysis has revealed many similarities Initially, it was unclear which subunits might engage this activ- between the three glutamate receptor families. However, unlike ity and, still, the search to identify the KAR subunit that mediates AMPA and NMDA receptors, KARs appear to also signal through this noncanonical signaling is not free of controversy. In dorsal

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root ganglia (DRG) neurons that exclusively express GluK1 and by KARs have only been found in a few central synapses, such as GluK5 subunits, noncanonical signaling was dependent on in MF to CA3 pyramidal neurons (Castillo et al., 1997; Vignes and GluK1 rather than GluK5 (Rozas et al., 2003). Subsequent Collingridge, 1997), the contacts between Schaffer collaterals studies found that KAR-mediated modulation of IAHP, an action and CA1 hippocampal interneurons (Cossart et al., 1998; Frerk- provoked by the noncanonical signaling of KARs (Melyan et al., ing et al., 1998), between parallel fibers and Golgi cells in the 2002), was absent in GluK2- (Fisahn et al., 2005) or GluK5- cerebellum (Bureau et al., 2000), at thalamocortical connections (Ruiz et al., 2005) deficient mice. However, more recent studies (Kidd and Isaac, 1999), in the basolateral amygdala (Li and reported that noncanonical signaling persisted in GluK5 and Rogawski, 1998), in the synapses between afferent sensory GluK4–GluK5 knockout (KO) animals (Fernandes et al., 2009). fibers and dorsal horn neurons in the spinal cord (Li et al., Indeed, expression of GluK1 in SHSY5 neuroblastoma cells 1999), and those of parallel fibers and cerebellar Golgi cells was sufficient to reconstitute metabotropic activity of KARs, as (Bureau et al., 2000). In all these synapses, the characteristic evaluated by the G protein and PKC activation inducing internal- slow kinetics is a predominant feature of the EPSCKAR, probably ization of KARs from the membrane (Rivera et al., 2007). Recent providing integrative capacities to information transfer clearly experiments confirmed the involvement of GluK1 in the metabo- unfulfilled by other glutamate receptors (Frerking and Ohliger- tropic control of glutamate release (Segerstra˚ le et al., 2010; Sal- Frerking, 2002; Pinheiro et al., 2013). For instance, O-LM inter- men et al., 2012). However, a biochemical interaction between neurons are a somatostatin interneuronal subtype at the stratum

GluK5 and a Gaq protein was identified in biochemical experi- oriens that processes glutamatergic inputs through KARs, ments (Ruiz et al., 2005). These data would in principle indicate which endow these cells with the ability to follow inputs at the that the subunit interacting with G proteins might be GluK5, theta frequency (Goldin et al., 2007). In addition, recent data indi- either directly or indirectly. There are additional issues that cate that GluK1-containing KARs in a subset of stratum radiatum appear at odds with this idea. The involvement of Gq protein interneurons mediate feedforward inhibition of pyramidal cells. does not fit with the PTx sensitivity of the metabotropic actions The output of these interneurons is enhanced during both low- of KARs described to date (see Rodrigues and Lerma, 2012 frequency-evoked stimulation and natural-type firing patterns. and references therein) but, rather, the PTx sensitivity suggests During this activity, the threshold for the induction of theta-burst that Gi or Go proteins are likely to be involved in the metabotropic LTP is raised. In this way, such KAR-mediated input promotes a actions of KARs. However, the concomitant involvement of PLC shift in the dynamics of synaptic transmission in favor of inter- and PKC in most of the metabotropic effects described to date neuronal output onto CA1 pyramidal neurons (Clarke et al., rules out the participation of Gi, leaving the Go protein as the 2012). only strong candidate to mediate these effects (e.g., Rozas A striking impact on neuronal excitability of postsynaptic et al., 2003). Nevertheless, some effects induced by KA are KARs, acting through their noncanonical signaling, is provided contingent on the inhibition of adenylate cyclase and the subse- by the regulatory action of the slow afterhyperpolarization cur- quent reduction in cAMP would involve Gi protein activation, as rent (IsAHP: Melyan et al., 2002, 2004). The IsAHP activates upon also described (Gelsomino et al., 2013; Negrete-Dı´az et al., bursts of action potentials and it is generated by voltage-sensi- 2006). Available data clearly show that subunit composition tive Ca2+-dependent K+ channels. It has a slow decay time as alone cannot define the signaling mode triggered by KARs, it may last for several seconds, it is activated in proportion to pointing to interacting partners as candidates likely to determine the number and frequency of action potentials (Lancaster and the mode of action of KARs. However, the existence of proteins Adams, 1986), and it underlies spike frequency adaptation that functionally couple KARs and G proteins remains to be (Figure 2). At Schaffer-CA1 pyramidal cell synapses, at which demonstrated. no EPSCKAR has been documented (Lerma et al., 1997; Castillo It should be also taken into account that some at odds data et al., 1997; Frerking et al., 1998; Cossart et al., 1998), nanomolar has been published pointing out that at least part of the nonca- concentrations of KA cause long-lasting inhibition of IAHP nonical signaling triggered by KARs may be indirect (Lourenc¸o through the direct activity of KARs. This effect is mimicked by et al., 2011). Regardless of the specific mechanisms, it is now synaptic glutamate released from excitatory afferents at the clear that KARs can no longer be considered simply as ligand- CA1 synapses (Melyan et al., 2004; Chamberlain et al., 2013). gated ion channels. The increasing number of activities known Pharmacological evidence indicates that this inhibition involves to be mediated by KARs through this noncanonical signaling, the noncanonical signaling engaging Gi/o protein and PKC acti- as described below, indicates that this dual signaling is one of vation (Melyan et al., 2002) and probably PKA and downstream the main factors underlying the diverse actions of KARs reported activation of MAP kinases (Grabauskas et al., 2007). The inhibi- over the years. tion of both the slow and medium IAHP by KAR activation in- creases the firing frequency of these neurons, largely enhancing Roles in Synaptic Transmission and Network Excitability circuit excitability (Fisahn et al., 2005; Ruiz et al., 2005). Like

Postsynaptic Kainate Receptors KAR-mediated EPSCs, inhibition of IAHP has been observed in Unlike AMPAR-mediated currents, the activation of postsynaptic MF-CA3 pyramidal cell synapses (Ruiz et al., 2005; Fisahn KARs by synaptically released glutamate yields small amplitude et al., 2005) and, therefore, both signaling modes can coexist EPSCs, with slow activation and deactivation kinetics (see within the same synapses. Thus, a short train of stimuli to the Figure 1; Castillo et al., 1997). Moreover, while AMPARs and mossy fibers could not only directly depolarize the postsynaptic NMDARs are localized to the postsynaptic density of the vast membrane but also increase neuronal excitability by prevent- majority of glutamatergic synapses in the brain, EPSCs mediated ing spike adaptation. Interestingly, both the ionotropic and

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A MF-CA3 EPSCs B GABAergic IPSCs Figure 3. Presynaptic KARs Modulate Synaptic Neurotransmitter Release in a Untreated +Glu uptake inhibitor Bidirectional Manner and Both Inotropic and Noncanonical Metabotropic Activity Are Involved (A) In the mossy fiber to CA3 synapses, activation +KAR KAR of KARs is responsible of part of the frequency Antagonist Antagonist facilitation, such that the inclusion of a KAR Control Control Control antagonist reduces the synaptic responses to the +KAR second and subsequent stimuli but not the first Antagonist EPSC. At the bottom of each panel, the variation in ΔQ (Cont-Anta) synaptic current charge (DQ) due to the activation of KARs is indicated. (B) Bidirectional modulation of evoked IPSCs by KARs. Superimposed traces illustrating evoked IPSCs obtained under control conditions (black traces) and in the presence of a KAR inhibitor (UBP302) (blue traces) in slices untreated or treated with D,L-TBOA, an inhibitor of glutamate reuptake (based on Bonfardin et al., 2010). In the first case, GABA release is facilitated by tonic activity of KARs, while in the second (larger concentrations of extracellular glutamate) GABA release is inhibited. metabotropic actions are segregated in the neurite tree and are higher affinity for glutamate, efficiently maintaining spike gener- independent of each other (Rozas et al., 2003), a result further ation at granule cells. Such effects should be explored at supported by the use of mice lacking individual KAR subunits different synapses given that this homeostatic regulation has (Ruiz et al., 2005; Fernandes et al., 2009) or pharmacologically also been observed in climbing fibers to Purkinje cell synapses antagonized ion channel activity (Pinheiro et al., 2013). This rein- (Yan et al., 2013), which may indicate it to be a more universal forces the idea that KARs may engage metabotropic and iono- mechanism than originally thought. tropic signaling in an independent manner. Presynaptic Kainate Receptors Together, the evidence provided so far demonstrates that The unconventional hypothesis that KARs could also play a role postsynaptic KARs regulate neuronal excitability both by pro- as presynaptic modulators of neurotransmitter release was ducing long-lasting depolarization and by inhibiting IAHP through prompted by the observation that the pharmacological activa- a segregated G protein-coupled pathway. The efficiency of tion of KARs modulated Ca2+-dependent glutamate release KARs in the regulation of neuronal excitability seems to rely on from synaptosomes, which are structures devoid of somatoden- repetitive synaptic activation rather than on single impulses, indi- dritic elements (Chittajallu et al., 1996). Since then, much effort cating that postsynaptic KARs are designed to modulate the has been devoted to determine the presynaptic role of KARs temporal integration of excitatory circuits. Similarly, there is and it is now widely accepted that functional presynaptic KARs now compelling evidence that KARs elicit sufficient charge play a crucial role in the control of neurotransmitter release transfer to have a substantial impact on synaptic function wher- (Lerma, 2003). Indeed, it is now known that presynaptic KARs ever they are expressed. For example, the kinetics of the EPSP modulate neurotransmitter release in a bidirectional manner, mediated by KARs is sufficiently slow to allow substantial tonic not only at excitatory but also at inhibitory synapses. depolarization during even modest presynaptic activity (Frerking KAR activation modulates GABAergic transmission in a com- and Ohliger-Frerking, 2002; Sachidhanandam et al., 2009; see plex cellular and subcellular manner, and both depression and Figure 1). But not only has the long ionotropic activity had an facilitation of GABA release have been reported (Figure 3). The impact on synaptic integration. The importance of the metabo- question then arises as to which event takes preference over tropic actions of KARs has also been recently put forward by the other and under what circumstances? Early indications of showing that the plastic changes in the KAR-mediated synaptic KA-induced depression of inhibition in the hippocampus (Slo- component could modify the degree of inhibition of IAHP in CA3 viter and Damiano, 1981) were confirmed by the demonstration pyramidal neurons. Chamberlain and associates (Chamberlain that KARs can inhibit GABA release (Rodrı´guez-Moreno et al., et al., 2013) showed that induction of LTD of the KAR-mediated 1997; Vignes et al., 1998). The depression of inhibition induced EPSC induced by natural pattern of stimulation relieves the KAR- was shown to be sensitive to PTx and to inhibitors of both PLC induced inhibition of IAHP, resulting in further attenuation of and PKC, leading to the postulate that KARs participated in neuronal responses to subsequent inputs. These data indicate unconventional events at presynaptic sites that most likely that KARs may exert a major role in regulating neuron excitability involve a metabotropic signaling pathway rather than ion flux and that although long-lasting plastic modulation of these recep- (Rodrı´guez-Moreno and Lerma, 1998). This idea was later sup- tors does alter their ionotropic function, their concomitant ported by measuring GABA release in synaptosomes (Cunha metabotropic activity becomes a dominant factor, at least et al., 1997, 2000; Perkinton and Sihra, 1999) and it has been under certain experimental conditions such as high-frequency observed in other structures such as the amygdala (e.g., Braga (10–20 Hz) activity. et al., 2004), neocortex (Ali et al., 2001), globus pallidus (Jin Also, KARs have been recently shown to be subject to homeo- and Smith, 2007), and hypothalamic supraoptic nucleus (Bonfar- static plasticity (Yan et al., 2013) in that the KAR-mediated EPSC din et al., 2010). However, CA1 interneurons become overacti- at mossy fiber to cerebellar granule cell synapses was enhanced vated by exogenous KA through somatodendritic KARs, leading after network activity blockade (either by TTx or genetically to the paradox of KA inducing both overflow (Frerking et al., removing AMPARs). This phenomenon relies on the enhanced 1998; Cossart et al., 1998) and inhibition of GABA release. Pre- expression of GluK5 subunits that produces receptors with a synaptic and somatodendritic KARs seem to coexist, presenting

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Figure 4. Kainate Depresses Hippocampal A B Inhibition and Generates Epileptic Activity In Vivo (A) Arrangement of recording and stimulating electrodes in vivo. In this experiment, a micro- dialysis probe implanted in the region allowed kainate to be slowly introduced into the extracel- lular fluid. The degree of GABAergic inhibition could be tested by the paired-pulse test, recording field potentials from the CA1 pyramidal layer through an extracellular electrode. (B) Stimulation of the Schaffer collateral pathway evokes the synchronous firing of a large number of C CA1 pyramidal cells (the sharp negative wave indicated by an asterisk in the first evoked poten- tial). This initial firing of the neuronal population activates a population of inhibitory interneurons that feedback onto the CA1 pyramidal neurons, such that a second stimulus arriving during the inhibitory phase (40 ms later) is unable to induce CA1 neuron firing, evident by the absence of a population spike in response to the second stimulus under control conditions. After perfusion of kainate through the dialysis probe (3 mM in the perfusate, probably 10% of this concentration reaches the extracellular fluid), the population spike in the second response progressively develops, indicating a failure in the inhibition of pyramidal cells. (C) After prolonged perfusion of kainate, ongoing epileptic activity develops that is characterized by the presence of interictal spikes in the EEG. The insert in yellow represents a 1 s period over an expanded time base (modified from Rodrı´guez-Moreno et al., 1997). distinct pharmacological profiles and subunit compositions and of interictal epileptic spikes in the electroencephalogram (EEG) using different signaling pathways (Rodrı´guez-Moreno et al., (see Figure 4; Rodrı´guez-Moreno et al., 1997). 2000; Mulle et al., 2000; Christensen et al., 2004; Maingret Evidence that presynaptic KARs mediate tonic inhibition of et al., 2005). Thus, while somatodendritic KARs mediate part of GABAergic transmission has also been obtained from the hypo- the synaptic input from Schafer collaterals, presynaptic KARs thalamic supraoptic nucleus, where it involves a PLC-dependent are activated by synaptically released glutamate and they metabotropic pathway (Bonfardin et al., 2010). During develop- reduce the inhibitory input to pyramidal cells (Min et al., 1999). ment, tonic activation of presynaptic GluK1-containing KARs Thus, KARs play a fundamental role in the performance of also depresses GABA release from hippocampal MF in a G neuronal circuits, as exemplified in the hippocampus. protein- and PLC-dependent manner (Caiati et al., 2010). Thus, As for other aspects of KAR activity, the mechanism by which regardless of the mechanism, there is a growing body of KARs modulate inhibitory input to pyramidal neurons is not free evidence that activation of presynaptic KARs depresses of controversy. It has been reported that inhibition of GABA GABAergic transmission, either after exogenous agonist appli- release from CB1 receptor-expressing interneurons induced by cation or through endogenous released glutamate. However, KAR activation depended, at least in part, on cannabinoid-1 paired recordings of interneurons and CA1 pyramidal cells also

(CB1) and GABAB receptors strategically situated at the presyn- show that endogenous activation of KARs can facilitate GABA aptic GABA boutons (Lourenc¸o et al., 2010, 2011). It was release at some synapses (Jiang et al., 2001). Further evidence proposed that synaptically released glutamate induced the post- that presynaptic KARs exert such a facilitatory effect on GABA synaptic release of endocannabinoids and the extracellular release has been gathered from hippocampal interneurons accumulation of GABA. This conclusion contradicts the observa- (Mulle et al., 2000; Cossart et al., 2001), as well as in several other tion of the inhibitory effect of KA on GABA release in interneuron- regions of the CNS like the neocortex (Mathew et al., 2008) and pyramidal cell pairs in the presence of antagonists of CB1 (e.g., hypothalamus (Liu et al., 1999). In contrast to the inhibitory

AM251) or GABAB (e.g., CGP55845) receptors (Daw et al., 2010). effects, the facilitation of GABA release by presynaptic KARs is Perhaps these disparate conclusions may come from the com- likely to involve the conventional ionotropic activity of these bined or independent antagonism of both types of receptors, receptors (reviewed in Rodrigues and Lerma, 2012). This seems but even when both receptors were blocked, a fraction of inhibi- to at least be the case for endogenous activation of KARs in the tion of GABA release seems to rely on KAR activity (Lourenc¸o hypothalamic supraoptic nucleus. It was shown in an elegant et al., 2011). Whatever the fraction of GABA release affected study that the increase in the ambient levels of glutamate, either by KAR activation, one can consider that presynaptic KARs will associated to a physiological reduction in astrocyte cover or due be activated by glutamate released during intense periods of to the blockade of glutamate transporters, switches facilitation activity in vivo. This will result in the depression of GABA release, to inhibition of GABAergic release (Bonfardin et al., 2010) likely leading to a state of overexcitability that could have impor- (Figure 3). Interestingly, while facilitation was prevented by phi- tant consequences on the circuit performance, making it more lantotoxin (a blocker of Ca2+-permeable receptors), the inhibitory seizurogenic by dampening inhibition. Indeed, this has been effect involved PLC. Thus, the net result of activating presynaptic proven to occur in the hippocampus in vivo when a low concen- KARs by endogenous glutamate may depend on the glutamate tration of KA is slowly dialyzed into the extracellular fluid. This concentration actually reaching the presynaptic KARs, which causes a depression of synaptic inhibition and the appearance will ultimately depend on the magnitude of glutamate spillover

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arising from different patterns of synaptic activity coupled to the boring MF synapses influences the threshold to induce LTP at astrocyte uptake capacity. these synapses (Schmitz et al., 2003). NMDARs implement the This hypothesis is further substantiated by data from the cer- associative properties of LTP. However, the contribution of ebellum, where bidirectional modulation of transmitter release NMDARs to the induction of LTP in the CA3 field is quite modest has also been found. Synaptically activated presynaptic KARs and one might think that the presence of KARs at these synapses facilitate and depress transmission at parallel fiber synapses maintains the general properties of LTP unaltered. (Delaney and Jahr, 2002). Activation of presynaptic KARs by syn- While the facilitation of glutamate release has clear functional aptically released glutamate at parallel fibers facilitates gluta- implications, it remains unclear under what circumstances the mate release to both interneurons (e.g., stellate or basket cells) suppression of glutamate release by KARs may fulfill a significant and Purkinje cells when these fibers are subjected to a regime role. Interestingly, it seems that during development, the inhibi- of low-frequency stimulation. By contrast, with high-frequency tory modulation of glutamate release may shape synaptic prop- stimulation, the synapses onto inhibitory interneurons are erties (Lauri et al., 2006; see below), and it has been observed depressed, while synapses at Purkinje cells are still facilitated. that long and strong trains of afferent activity depress rather Such differential sensitivities to the frequency of these two syn- than facilitate synaptic transmission (Schmitz et al., 2001), a apses may regulate the excitation/inhibition balance of Purkinje mechanism that may be active under physiological conditions. cells and, therefore, cerebellar output. Thus, at some structures, Facilitation of glutamate release at MF-CA3 synapses is KARs bestow computational properties to circuits according to mimicked by applying low concentrations of exogenous KA the activity regime of afferent inputs. (Schmitz et al., 2000; Kamiya and Ozawa, 2000). Higher concen- Presynaptic regulation of excitatory transmission by KARs has trations of KA depress synaptic transmission not only at MF-CA3 been studied extensively at MF-CA3 synapses. At these synap- synapses but also at synapses between Schaffer collaterals and ses, presynaptic KARs are implicated in the characteristic fre- CA1 pyramidal cells (Chittajallu et al., 1996; Kamiya and Ozawa, quency-dependent facilitation of MF excitatory transmission 1998; Vignes et al., 1998; Frerking et al., 2001) and those of the (Schmitz et al., 2001; Lauri et al., 2001; Contractor et al., 2001; associational/commissural pathway terminating on CA3 neurons Pinheiro et al., 2007), a phenomenon initially ascribed to the re- (Salmen et al., 2012). This inhibition is accompanied by a reduc- sidual intraterminal calcium. Since KAR antagonists attenuate tion in presynaptic Ca2+ (Kamiya and Ozawa, 1998; Salmen the potentiation of the second EPSC during high-frequency et al., 2012), and since it is sensitive to G protein blockers, this trains (e.g., 25 Hz; Schmitz et al., 2001), the synaptic activation inhibition is unlikely to involve presynaptic depolarization, but it of presynaptic KARs must be quite fast (10–30 ms), indicating is more likely to be contingent on noncanonical signaling (Frerk- that KARs should be found near the active zone. Indirect evi- ing et al., 2001; Negrete-Dı´az et al., 2006; Salmen et al., 2012). dence suggests that the facilitation of glutamate release may The inhibition of glutamate release at Schaffer collaterals-CA1 occur through the depolarization of presynaptic terminals synapses does not involve protein kinases but, rather, a mem- (Schmitz et al., 2001) that should enhance action potential-driven brane-delimited action that probably involves the direct inhibi- Ca2+ influx (Kamiya et al., 2002; Lauri et al., 2003). The reduction tion of presynaptic Ca2+ channels by G protein gb subunits (De of synaptic facilitation by a blocker of Ca2+-permeable KARs Waard et al., 1997). The inhibitory effects of KARs upon tonic (Lauri et al., 2003) also points to a contribution of direct Ca2+ activation by endogenous glutamate at these two hippocampal entry through these receptor channels, although Ca2+ mobiliza- synaptic populations have been observed during development tion from intracellular stores may also add to this use-dependent and involve KAR metabotropic signaling (Lauri et al., 2005, facilitation of glutamate release (Lauri et al., 2003; Scott et al., 2006; Sallert et al., 2007). Tonic activation of presynaptic KARs 2008). Nevertheless, these conclusions have been challenged in the adult brain also inhibits glutamate release in the rat globus by the indication that presynaptic KARs are insufficient to facili- pallidus, once again mediated by a presynaptic Gi/o-protein- tate glutamate release at MF-CA3 synapses, attributing the phe- coupled and PKC-dependent mechanism (Jin and Smith, 2007). nomenon to the activation of recurrent CA3 network activity What now seems clear is that presynaptic KARs modulate (Kwon and Castillo, 2008). However, blockade of postsynaptic transmitter release in a bidirectional manner: facilitation probably KARs at MF-CA3 synapses with newly available compounds occurs through their ionotropic activity, while inhibition seems to (e.g., UBP310) had no effect on presynaptic facilitation (Pinheiro involve noncanonical metabotropic signaling. It is possible that et al., 2013), a result similar to that observed in double GluK4/ the threshold to activate one or other KAR signaling pathways GluK5 mice, in which there is no deficit in short-term plasticity, would determine physiological responses. In summary, the pre- whereas postsynaptic KAR-mediated responses are totally lost synaptic modulation of both glutamate and GABA release (Fernandes et al., 2009). Therefore, in the absence of further together with the postsynaptic regulation of neuronal excitability evidence against it, it should be concluded that part of the syn- clearly demonstrates that KARs are endowed with diverse aptic facilitation observed at MF-CA3 synapses is due to the capacities. These activities enable them to fine-tune synaptic activation of presynaptic facilitatory KARs. Considering that pre- function and regulate neuronal network activity in the adult brain, synaptic KAR function has been assessed indirectly, direct elec- bestowing them with a much broader role at synapses than the trophysiological recording from these presynaptic structures simple transfer of information. may clarify the issue of whether or not ionotropic facilitatory Role of Kainate Receptors during Development KARs are present at MF boutons. KARs are expressed strongly in the brain during development in Conclusive evidence indicates that this mechanism imposes a complex cell-type-specific manner. The properties of synap- associative properties to MF-LTP, since the activity in neigh- ses during development differ significantly from those at mature

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stages and it is now known that presynaptic KARs contribute to lular space in which it is found, displaying lower motility as the these changes. free extracellular space diminishes (Tashiro et al., 2003). In this The expression of KARs, and particularly of GluK1 subunits, regard, KARs may represent sensors for the axonal filopodia to increases markedly and peaks during the first week of life in probe their immediate environment and, hence, it may be essen- rodents (Bahn et al., 1994). In immature hippocampal CA1 syn- tial for guidance and the formation of synaptic contacts. apses, the tonic activation of KARs by ambient glutamate keeps Together, these data demonstrate a critical role for KARs in the the probability of release low (Lauri et al., 2006). However, a burst development of synaptic connectivity and in the maturation of of synaptic activity produces strongly facilitating postsynaptic neuronal networks. In particular, how altering KAR activity during responses, a facilitation that is not only abolished in the presence development highlights the key role fulfilled by these receptors of a KAR antagonist but also later in development. Interestingly, when synaptic networks are established. However, we are only this change is recapitulated by inducing LTP and it seems that just beginning to understand the role of KARs in neuronal devel- the tonic stimulation of KARs by ambient glutamate is no longer opment and maturation, and the exact mechanisms underlying possible under each of these circumstances, changing the short- such events remain not defined. term synaptic dynamics. It is possible that the lower ambient glutamate contributes to the lack of tonic KAR activation after Putative Roles of KARS in Brain Disease the first postnatal week. However, it does seem that the affinity Abnormalities in glutamatergic neurotransmission are consid- of the receptor actually changes, making it less sensitive to the ered to be an important factor contributing to neurodegenerative agonist. Indeed, it has been claimed that a change in an isoform and mental disorders (e.g., Frankle et al., 2003). Kainate recep- of the GluK1 subunit in KARs is responsible for this lower affinity tors have been linked to a number of brain disorders such as (Vesikansa et al., 2012). The inhibition of synaptic release under epilepsy, schizophrenia, and autism, yet their role in brain pathol- these circumstances seems to be mediated by noncanonical ogies appears at times contradictory. Although the experimental KAR signaling. Another interesting situation in which a change data now available indicate a number of putative roles for KARs in the properties of KARs takes place during development is in in mood disorders, the data available are not free of caveats (see CA3 interneurons, where the firing rate is controlled by the Table 2).

KAR-mediated tonic inhibition of IAHP during the first postnatal Mood Disorders week (Segerstra˚ le et al., 2010). One more example of how Perhaps the most fascinating results come from the studies that KARs may control network activity during development is pro- potentially connect KARs with schizophrenia and bipolar disor- vided by the reduced glutamatergic input to CA3 pyramidal cells ders. On the one hand, postmortem studies provided evidence following tonic KAR activation and the simultaneous facilitation of a change in KAR subunits in schizophrenic brains (Benes of glutamate release onto CA3 interneurons (Lauri et al., 2005). et al., 2001), although these were not corroborated in other This action permits network bursting in the developing hippo- studies. For instance, a careful quantitative study of glutamate campus. All in all, these data imply a role for KARs in driving receptor mRNA expression failed to detect any change in KAR network activity during maturation, when synchronous neuronal subunit expression in dissected thalamic nuclei from the brains oscillations are important for the development of synaptic cir- of subjects diagnosed with schizophrenia (Dracheva et al., cuits (e.g., Zhang and Poo, 2001). 2008). On the other hand, postmortem gene expression profiling KARs also seem to contribute to the development of neuronal indicated that in the hippocampus, parahippocampus, and the connectivity by guiding the morphological development of the prefrontal cortex, at least, there is a decrease in the mRNA- neuronal synaptic network (i.e., the tracks and the formation of encoding GluK1 subunits (Scarr et al., 2005). Obviously it is early synaptic contacts). In GluK2-deficient animals, the func- difficult to evaluate the availability of protein from mRNA quanti- tional maturation of MF-CA3 synaptic contacts that normally fication, and given the absence of a specific GluK1 antibody, occurs between postnatal day 6 (P6) and P9 is delayed (Lanore these data await further verification. et al., 2012). In the early contact and rearrangement stages, Recent GWAS studies of thousands of cases indicated a poly- growth cone motility is essential for the axon to explore its envi- genic basis to schizophrenia, identifying SNPs that are shared ronment and find its appropriate synaptic targets (Goda and with bipolar disorder but not with other nonpsychiatric diseases Davis, 2003). In the developing hippocampus, KARs bidirection- (Ripke et al., 2011; Sklar et al., 2011). The common involvement ally regulate the motility of filopodia in a developmentally regu- of several genes in a disease complicates the reproduction of lated and concentration-dependent manner, increasing filopodia those diseases in experimental models, as it would not be ex- motility upon activation with low concentrations of KA and pected that a single mutation could fully reproduce the syn- decreasing it in the presence of high concentrations of KA drome. In the case of KARs, this is exemplified by the fact that (Tashiro et al., 2003). These data support a two-step model of an SNP for Grik4 (rs1954787) is more abundant in subjects re- synaptogenesis, whereby low concentrations of glutamate early sponding to antidepressant treatment with a serotonin uptake in- in development enhance motility by activating KARs to promote hibitor (citalopram) than in patients that do not (Paddock et al., the localization of synaptic targets. Having established the 2007). This SNP is located in the 30 region of the first intron of nascent synapse, the increase in glutamate concentrations as Grik4 gene and, while it does not directly affect the protein a consequence of the reduction in extracellular volume may sequence, it seems to alter gene expression. Similarly, there then reduce filopodia motility, prompting stabilization of the con- are data suggesting that Grik3 might be a susceptibility gene tact (Tashiro et al., 2003). This model is also consistent with the for major depressive disorder, whereby the SNP T928G observation that filopodia motility is related to the free extracel- (rs6691840) that causes an S to A alteration in the extracellular

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Table 2. KARs Most Salient Linkage to Mood Disorders Behavioral Gene Data Linked Disease Test in KO References Grik1 Upregulated expression Epilepsy No Sander et al., 1997; Izzi et al., 2002; Li et al., 2010; Lucarini et al., 2007 Grik2 Modest linkage Autism No Jamain et al. 2002; Shuang et al., 2004; Szatmari et al., 2007; Freitag 2007; but see Dutta et al., 2007 Grik2 Deletion of exons 7 and 8 Mania, mild mental No Motazacker et al., 2007; Shaltiel et al., 2008; Lanore et al., 2012 retardation Grik2 Mapping susceptibility locus Schizophrenia Yes Beneyto et al., 2007; Shaltiel et al., 2008; but see Shibata et al., 2002, 2006 Grik2 mapping Huntington No MacDonald et al., 1999; Chattopadhyay et al., 2003; but see Lee et al., 2012 and Diguet et al., 2004 Grik3 SNP T928G (rs6691840) Schizophrenia No Begni et al., 2002; Kilic et al., 2010; Ahmad et al., 2009; Grik3 SNP T928G (rs6691840) Major depression No Schiffer and Heinemann, 2007; Wilson et al., 2006 Grik4 Treatment response Depression No Paddock et al., 2007 Grik4 14 bp deletion/insertion Bipolar disorder Yes Pickard et al., 2008; Catches et al., 2012; Lowry et al., 2013 variant Grik4 SNPs rs2282586 and Protection against Yes Pickard et al., 2006 rs1944522 Schizophrenia domain of GluK3, is in linkage disequilibrium with recurrent major clusions can be reached without more precise information of the depressive disorder patients (Schiffer and Heinemann, 2007) role of these subunits in general brain physiology. However, and subjects with schizophrenia (Begni et al., 2002; Kilic et al., recent studies using experimental models have started to assess 2010; Djurovic et al., 2009; Ge´ cz et al., 1999). Indeed, the distri- how the absence of one of these genes affects behavior. The bution of the GG homozygous genotype was significantly higher ablation of Grik4 in mice results in marked hyperactivity (Catches in schizophrenia patients than in controls (Ahmad et al., 2009; et al., 2012; Lowry et al., 2013), one of the endophenotypes of Kilic et al., 2010). However, this amino acid change does not patients with bipolar disorders, which has been interpreted as have any detectable functional consequence in the receptor if lack of GluK4 activity has an anxiolytic and antidepressive- (Schiffer et al., 2000), although it could convey aberrant gene like effect (Catches et al., 2012). Anxiety and depression are con- dosage and/or unequal allele expression (Schiffer et al., 2000; current with bipolar disorders, and these data would in principle Wilson et al., 2006). Indeed, mRNAs for GluK3 and other gluta- support the hypothesis that GluK4 hyperactivity could be a hall- mate receptors are reduced in the frontal cortex of schizophrenic mark of bipolar phenotypes. However, genetic data from bipolar subjects (Sokolov, 1998; but see Meador-Woodruff et al., 2001). patients seem to refute this conclusion. In a case control associ- As for other subunits, GluK3 gene expression is developmentally ation study, two SNP haplotypes (rs2282586 and rs1944522) regulated and aberrant gene dosage during development may exhibited a protective effect against bipolar disorder in a diverse impact disease in adulthood (Wilson et al., 2006). Thus, further Scottish population (Pickard et al., 2006). Subsequent studies experiments using transgenic animals are warranted. identified a 14 bp deletion/insertion variant in the 30 UTR of the A clear example of gene dosage is provided by trisomy of Grik4 gene in subjects carrying a protective haplotype with a sig- chromosome 21, leading to Down syndrome. Grik1, the gene nificant association to the risk of bipolar disorders (Pickard et al., coding for GluK1 subunits, is located on human chromosome 2008). Surprisingly, the deletion allele was negatively associated 21q22.1, and genetic mapping places Grik1 in the vicinity of with bipolar disorder and it resulted in an increase in the abun- genes coding for APP and super oxide dismutase (SOD1; Gregor dance of both GluK4 mRNA (Pickard et al., 2008) and protein et al., 1994). However, linkage analysis failed to detect any asso- in the hippocampus and prefrontal cortex (Knight et al., 2012). ciation with familial amyotrophic lateral sclerosis and there are This resulted from the fact that the mRNA bearing the deletion no data indicating any role for GluK1 gene disequilibrium dosage seems to be more stable and persistent than that bearing the in Down syndrome. insertion, resulting in an increase in GluK4 protein of up to Based on multiple regression analyses, it appears that the 90% in the hippocampus and 40% in the cortex of the human effects of anxiety and depression treatment are significantly brain. and independently associated with the Grik4 gene (Paddock Consequently, one would expect that mice either deficient for et al., 2007). An association was also observed in female patients this gene or with GluK4 hypoactivity would display behavior with markers in Grik1. Together, these data indicate that reduced associated to bipolar disorders rather than expressing an antian- expression of Grik1, Grik4, and other genes encoding KAR sub- xiolytic or antidepressive phenotype. Indeed, in the forced units could be implicated in mood disorders (but see Li et al., swimming test, immobility is reduced by a number of antide- 2008). However, the sign of this implication is clearly elusive pressant drugs in normal mice, indicating that such immobility and these linkages may be circumstantial given that causal may be read out of depressive-like behavior. As in GluK4 KO mutations have not yet been identified through linkage or candi- mice, GluK2-deficient animals show less immobility than wild- date gene association studies. It is becoming clear that no con- type (WT) mice, although chronic lithium treatment reduced

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immobility in these GluK2-deficient mice to the same extent as in 6q21 (McQueen et al., 2005), where Grik2 maps, and GluK2 WT mice (Shaltiel et al., 2008). If the lack of GluK2 were antide- mRNA expression is also reduced in the brain of bipolar patients pressive, it should occlude the action of lithium, as lithium has (Beneyto et al., 2007). Interestingly, Grik2 KO mice exhibit a no effect in normal subjects. Therefore, it is possible that less variety of behaviors, including hyperactivity, aggressiveness, immobility would reflect anxiogenicity rather than less depres- and sensitivity to psychostimulants, reproducing in mice the sion. Actually, this kind of test of behavioral despair was behavioral symptoms of mania in humans (Shaltiel et al., 2008). designed as a test for the primary screening of antidepressant However, it is not currently possible to infer whether GluK2 is drugs (Porsolt et al., 1977). Therefore, when using this test, it is involved in the pathophysiology of mania and/or susceptibility difficult to deduce an antidepressive state through less immo- to bipolar disorders, or if it is just related to some features of their bility without directly checking the action of the antidepressants. symptoms. Nevertheless, mice in which Grik4 is deleted also display a Mental Retardation schizophrenic phenotype and, indeed, GluK4 KO mice show In one of the eight genomic loci linked to nonsyndromic auto- impaired paired-pulse inhibition, mirroring one of the endophe- somal recessive mental retardation in a study of 78 consanguin- notypes of patients with schizophrenia (Lowry et al., 2013). eous Iranian families, gene defects were revealed precisely in an These data are in keeping with the presence of three SNPs of interval on chromosome 6116.1-q21. This locus contains 25 the Grik4 gene in a patient with chronic schizophrenia and mild annotated genes, including Grik2, which was screened for mental retardation (Blackwood et al., 2007, 2008; Pickard DNA mutations in patients with mental retardation. Only one et al., 2006). This patient was found to present a complex rear- single nonpolymorphic sequence change was detected, involv- rangement of a segment of chromosome 11, involving chromo- ing a deletion that removed exons 7 and 8 of the Grik2 gene somes 2 and 8. The Grik4 gene was disrupted at a breakpoint (Motazacker et al., 2007). Although a truncated GluK2 subunit situated at 11q23.3 and the expected outcome was the trunca- was generated, it was unable to contribute to functional recep- tion of all putative transcripts such that the protein encoded tors, suggesting a severe hypofunction in glutamatergic sig- would not be functional (Blackwood et al., 2007; Pickard et al., naling through KARs that would alter local brain circuits and 2006). This means that knocking out Grik4 would result in symp- induce cognitive impairment. An attractive hypothesis proposed toms of schizophrenia and/or mental disability. Indeed, the in this study was that defects in GluK2 signaling may be impor- GluK4 KO does present learning deficits (Lowry et al., 2013; tant for correct circuit maturation in areas important for higher but see Catches et al., 2012). Interestingly, treatment with neuro- brain functions, such as the hippocampus. This hypothesis leptic drugs seems to restore levels of GluK4 mRNA expression was recently tested in GluK2-deficient animals in which a delay that are abnormally low (ca. 50%) in the frontal cortex of schizo- in the functional maturation of MF to CA3 synaptic contacts phrenics (Sokolov, 1998). Clearly, SNPs found in the Grik4 gene occurs between P6 and P9 (Lanore et al., 2012). Although this as markers of schizophrenia and bipolar disorders confirm a role transient defect in synaptic transmission may be critical for cor- for this gene as a risk factor for mood disorders. The SNPs vary rect postnatal development, it is not clear how it may affect hip- with the disease, with SNPs at the center of the gene at chromo- pocampal performance in adults beyond the fact that the some 6q11 associated with schizophrenia and SNPs at the absence of KARs at MF to CA3 synapses alters the integrative gene’s 30 end associated with bipolar disorders. properties of the hippocampal trisynaptic circuit, which is impor- Clarification of aspects mentioned above is critical for envi- tant for memory acquisition in novel environments and some- sioning therapeutic opportunities. On the one hand, data from times for memory recall (Nakashiba et al., 2008). patients suggest that a pharmacologically mediated increase in Grik2 has also been associated with autism (Jamain et al., KAR activity might be beneficial to protect against bipolar disor- 2002; Shuang et al., 2004; Freitag, 2007). However, these find- ders, while on the other hand, behavioral data from mice (e.g., ings were inconclusive and could not be substantiated by further GluK4-deficient mice) may open the door to therapeutic oppor- genome-wide linkage studies in which only a modest positive tunities for antagonists (e.g., of GluK4). However, this latter linkage could be seen in families containing females (Szatmari approach would be detrimental to other phenotypes, such as et al., 2007). Indeed, other studies also failed to find associated schizophrenia. The uncertainty of interpreting behavioral data markers in individuals with autism spectrum disorder (Dutta in mice must also be born in mind and, as mentioned above, et al., 2007) and GluK2 KO mice have not been studied in terms reduced immobility of KO mice in the forced swimming test of this pathology. has been interpreted as antidepressant in some cases and as Huntington Disease a sign of mania in others. A number of studies have shown that glutamine repeats in Hun- A significant decrease in GluK2 mRNA expression has been tington disease (HD) only account for 50%–60% of the variance reported in schizophrenic subjects (Porter et al., 1997). Interest- at the age of onset (e.g., Snell et al., 1993). This fact prompted a ingly, this gene maps close to a locus of schizophrenia suscep- search for functional consequences in the age of onset of poly- tibility on chromosome 6 (6q16.3-q21) (Bah et al., 2004), morphisms associated with HD chromosomes. Among other although no association between this gene and schizophrenia genes, and given that excitoxicity is considered a potential could be demonstrated after studying 15 SNPs evenly distrib- mechanism for the cell death seen in HD, the Grik2 gene was uted over the entire Grik2 region, ruling out a major role of examined for its potential influence on the age of onset, particu- GluK2 in the pathogenesis of schizophrenia (Shibata et al., larly since it maps to chromosome 6q. More than 4% of the total 2002). However, several genome-wide studies have shown sig- variance could be attributed to variation in the GluK2 genotype, nificant linkage between bipolar disorders and chromosome representing 13% of the variance in the age of onset of HD not

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accounted for by CAG repeats (Rubinsztein et al., 1997). There- that antagonists of GluK1 (i.e., LY377770 and LY382884) prevent fore, it was concluded that a younger onset of HD is in linkage the development of epileptic activity in the CA3 area of hippo- disequilibrium with a variant of GriK2 or another gene in the re- campal slices in a model of pilocarpine-induced epileptiform gion (MacDonald et al., 1999; Chattopadhyay et al., 2003). To activity. Interestingly, GluK1 antagonists were equally effective reproduce these data in a larger population, the HD CAG repeats in abolishing epileptic activity in slices and in preventing seizures and the Grik2 TTA repeats were genotyped in a large (>2,900) as well as in abolishing seizures once established in vivo. In population of HD subjects (Snell et al., 1993; Lee et al., 2012). contrast, others (Khalilov et al., 2002) have indicated a potential No evidence of an influence of Grik2 polymorphisms on age at for GluK1 agonists as antieplieptic based on the overinhibition motor onset was found and, therefore, there was no support largely mediated by GluK1-containing receptors, which are for the role of Grik2 as a genetic modifier of the age of onset in enriched in hippocampal interneurons. HD. Similarly, a study of the susceptibility of GluK2-deficient The muscarinic agonist pilocarpine is used as a standard mice to 3-nitropropionic acid, a drug used to induce metabolic model to generate epileptiform activity in order to evaluate the failure and secondary excitotoxic HD-like damage, was also potential of anticonvulsant drugs (cf. Smolders et al., 2002 and inconclusive (Diguet et al., 2004). Therefore, despite efforts to references therein). One of the advantages of this model is that link GluK2 to HD, it seems unlikely that KARs are involved in it does not involve direct stimulation of KARs, thereby allowing the direct pathogenesis of this disease. the evaluation of the contribution of tonic KAR activation by Epilepsy ambient glutamate to the epileptic phenomena. It is likely that There are several lines of evidence strongly suggesting that multiple mechanisms may account for the involvement of KARs might be involved in the excitatory to inhibitory imbalances KARs in epilepsy. It is possible that the glutamate released due linked to epilepsy. Actually, KA injection has served as an animal to circuit hyperactivity may provoke both tonic activation of model that reproduces details of human temporal lobe epilepsy CA3 neurons and KAR-mediated depression of synaptic inhibi- (TLE). The inhibition of GABA release and the activation of post- tion. These two actions would be sufficient to generate a drastic synaptic KARs might account for the acute epileptogenic effect imbalance between excitation and inhibition, leading to hippo- of KA (Rodrı´guez-Moreno et al., 1997), although these events do campal seizures. A similar mechanism has been invoked in the not explain the chronic epilepsy generated months after KA amygdala to account for the therapeutic effects of topiramate treatment. Actually, the seizures provoked initiate a number of (Braga et al., 2009), an approved antiepileptic medicine. molecular changes and morphological rearrangements in struc- A linkage study of 20 families found a significant excess of the tures with a low epileptogenic threshold, such as the hippocam- Grik1 tetranucleotide polymorphism (nine ‘‘AGTA’’ repeats) in pus. For instance, it is well known that sprouting of glutamatergic members of families affected by idiopathic juvenile absence fibers takes place in both the KA model of TLE and in human epilepsy (Sander et al., 1997). This allelic variant of Grik1 prob- patients and, accordingly, a large number of aberrant synapses ably confers susceptibility to juvenile absence epilepsy, when are established de novo. These functional aberrant synapses superimposed on a background of strong polygenic effects. made on granule cells of the dentate gyrus are sprouted MFs The tetranucleotide polymorphism maps to the noncoding re- and they incorporate KARs, which provide a substantial compo- gion of the gene, close to regulatory sequences, and although nent of the excitatory input (Epsztein et al., 2005). Thus, aberrant it does not seem to affect receptor structure (Izzi et al., 2002), KAR-operated synapses formed under pathological conditions it could alter gene expression. However, as there is no evidence represent a morphological substrate likely to participate in the of this to date, this association may also be due to a hypothetical pathogenesis of TLE (Artinian et al., 2011). The data available epilepsy gene in this region in linkage disequilibrium with Grik1 from human epileptic tissue indicates an upregulation of GluK1 tetranucleotide repeats (Lucarini et al., 2007). Despite all the in the hippocampus of pharmacoresistant TLE patients (e.g., Li evidence linking KARs to epilepsy, to our knowledge no anti- et al., 2010), suggesting that rearrangements in neural circuits epileptic drugs have been developed to date based on KAR involving KARs could also take place in humans suffering epi- antagonists. lepsy. Although these data should be considered with care due Pain to the poor specificity of some KAR antibodies (e.g., GluK1), it KARs are expressed strongly in DRG cells and dorsal horn neu- raises the possibility of designing antiepileptic therapies based rons, pointing to a specific role for these receptors in sensory on the antagonism of KARs. transmission and pain. Indeed, KARs were targeted as potential Consistent with KARs influencing this imbalance, the genetic elements involved in pain transmission and kainate was demon- elimination of GluK2 subunits in mice reduced their sensitivity strated to depolarize primary afferents (Agrawal and Evans, to develop seizures after KA injections (Mulle et al., 1998), illus- 1986). Moreover, a pure population of KARs was initially isolated trating that these receptors contribute to the establishment of from DRG neurons that are likely to be C fiber nociceptors overexcitability by exogenous KA that leads to epilepsy. Simi- (Huettner, 1990). Molecular and electrophysiological character- larly, exogenous KA reduced GABA release in slices (Clarke ization of these neurons led us to conclude that these DRG et al., 1997; Rodrı´guez-Moreno et al., 1997), dramatically pre- KARs are made up of heteromeric GluK1 and GluK5 subunits venting the recurrent inhibition of hippocampal principal neurons (Sommer et al., 1992; Bahn et al., 1994; Rozas et al., 2003), in vivo and provoking epileptic activity (Rodrı´guez-Moreno et al., and since glutamate-induced currents are lost in GluK1-deficient 1997). According to these data, constituting the strongest evi- mice, this appears to be the only iGluR expressed in these cells dence of the potential therapeutic utility of KARs, a consortium (Mulle et al., 2000; Rozas et al., 2003). Although pain perception of academic and industry groups (Smolders et al., 2002) showed cannot be properly considered a disease, persistent or recurrent

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tnempolevedgnirudskrowtencitpanysfonoitarutaM apeutic trials appear to have been abandoned (see Bhangoo and Swanson, 2013 and references therein). Kainate Receptors Thus, the genetic linkage of KAR subunits to diseases are extremely illustrative as to the diseases that may be influenced or triggered by KARs, represent promising lines for further Postsynaptic depolarization Enhancemento f Presynaptic modulationo f studies into their mechanistic causes. However, much work re- at some excitatory synapses neuronal excitability Glu and GABA release mains to be done before definitive conclusions can be drawn regarding the exact roles of KARs in brain disease.

excitation and inhibition Perspective Balance between It is now apparent that KARs play different roles in synaptic transmission and its modulation to those fulfilled by other gluta-

Activity of Neuronal Circuits mate receptors, such as AMPARs and NMDARs (see Figure 5), yet there is still much to be learned concerning the role of KARs in brain performance. Several functional implications Brain Performance directly emanate from the role played by KARs as ion channel forming receptors at synapses, including a role in short- and Figure 5. Diagram Illustrating How KARs Could Influence Cognitive long-term synaptic plasticity. New and unexpected roles for Functions by Modifying Key Functional Features of Neuronal and KARs come from their capacity to signal though noncanonical Circuit Activity Any alteration in the regulation of these activities, including circuit maturation metabotropic pathway. Although the importance of both during development, may provoke sufficient disequilibrium as to lead to a signaling modes has been demonstrated in neuronal physiology, disease state. it is unclear which may be more relevant and under which cir- cumstances, something we hope will be revealed in the near pain is associated to a number of disorders of distinct origins and future. Similarly, it remains unclear which subunits may be pathophysiological bases, including neuropathic pain. Initial responsible for coupling to G proteins and how an ion channel support for the involvement of KARs in pain transmission came couples to and activates a G protein. These questions, relevant from the fact that several KAR antagonists possess analgesic to fully understand KARs, await further advances. activity in a number of animal models of pain. For instance, It is also necessary to more strictly examine the role of KARs SYM 2081 increases the latency of escape in the hot plate and in brain disease, as indicated by the linkage of SNPs and muta- chronic constriction injury tests, presumably acting as a func- tions in KAR encoding genes to several devastating diseases, tional antagonist (Sutton et al., 1999), whereas the antagonist such as schizophrenia and bipolar disorders, the most promising of GluK1-containing receptors, LY382884, decreases the fre- syndromes linked to KAR malfunction. Such studies should quency of paw licking induced by the subcutaneous injection benefit from the already abundant information of the roles of formalin (Simmons et al., 1998). In keeping with these results, played by KARs in synaptic physiology, and the availability of the ablation of Grik1 gene mitigates pain-associated behavior KO and transgenic models will be particularly beneficial in this (Ko et al., 2005; see Bhangoo and Swanson, 2013 for a review enterprise. Nevertheless, new models are still to be developed. and references therein). These experiments will reveal how KARs participate in normal Interestingly, the activation of primary afferent sensory fibers behavior and whether they are suitable targets for therapeutic produces a kainate receptor-mediated EPSC on the dorsal interventions. horn neurons (Li et al., 1999). As in the CNS, these synaptic re- The plethora of proteins able to interact with KARs, some of sponses are characterized by slow onset and decay time con- them demonstrated to be true ancillary proteins, opens a new stants. A remarkable feature of these KAR-mediated EPSCs is field of research to analyze their role not only in pacing affinity that they can only be elicited upon nerve stimulation at intensities and channel gating but also in the polarized trafficking of these strong enough to activate the high-threshold Ad and C fibers. receptors. How do they get into the presynaptic terminals? This feature raises the possibility that KARs may be exclusively How do they get into the synaptic spines? Is there a specific involved in nociceptive transmission at this level, a hypothesis role for abundant extrasynaptic KARs? Are all these protein- that received significant support when opiate agonists were protein interactions regulated by neuronal activity or any other shown to reduce the amplitude of the KAR-mediated EPSC in functional factors? dorsal horn neurons (Li et al., 1999). In addition, this receptor In summary, after 20 years of research following their func- subtype is also expressed by trigeminal neurons (Sahara et al., tional identification in CNS neurons, KARs remain vaguely 1997) and KARs are generally expressed along nociceptive path- defined entities. There is a lot of information available but under- ways, from DRG neurons to the cortex (see Wu et al., 2007 for a standing the functions of KARs still lags behind that of other review). The strong indications that GluK1 antagonists modulate glutamate receptors and a comprehensive model is still lacking. pain perception have led to several clinical trials to validate KARs The potential of these receptors as targets for new therapeutic as therapeutic targets for pain treatment (reviewed by Bhangoo interventions is extensive and could well represent just the tip and Swanson, 2013). While some of these demonstrated certain of an iceberg. The detailed study of currently available KAR-defi- efficacy, and positive results were reported in phases I and II for cient mice and the development of new animal models (e.g., migraine, postoperative pain, and analogous cases, these ther- conditional KOs and mice overexpressing KARs) should fuel

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progress in this area, perhaps unraveling how these receptors Braga, M.F.M., Aroniadou-Anderjaska, V., and Li, H. (2004). The physiological may more efficiently serve as therapeutic targets. role of kainate receptors in the amygdala. Mol. Neurobiol. 30, 127–141. Braga, M.F., Aroniadou-Anderjaska, V., Li, H., and Rogawski, M.A. (2009). Topiramate reduces excitability in the basolateral amygdala by selectively ACKNOWLEDGMENTS inhibiting GluK1 (GluR5) kainate receptors on interneurons and positively modulating GABAA receptors on principal neurons. J. Pharmacol. Exp. Ther. The authors’ research is supported by grants to J.L. from the Spanish MICINN 330, 558–566. (BFU2011-24084), CONSOLIDER (CSD2007-00023), and Prometeo/2011/ 086. J.M.M. was supported by a PhD fellowship from the Portuguese Bureau, I., Dieudonne, S., Coussen, F., and Mulle, C. (2000). Kainate receptor- Fundac¸a˜ o para a Cieˆ ncia e a Tecnologia. Discussion and input from the mediated synaptic currents in cerebellar Golgi cells are not shaped by diffusion members of J.L.’s laboratory are warmly acknowledged. of glutamate. Proc. Natl. Acad. Sci. USA 97, 6838–6843.

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