Presynaptic LTP and LTD of Excitatory and Inhibitory Synapses

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Pablo E. Castillo

Dominick P.Purpura Department of Neuroscience Albert Einstein College of Medicine, Bronx, New York10461 Correspondence: [email protected]

Ubiquitous forms of long-term potentiation (LTP) and depression (LTD) are caused by enduring increases or decreases in neurotransmitter release. Such forms or presynaptic plasticity are equally observed at excitatory and inhibitory synapses and the list of locations expressing presynaptic LTPand LTD continues to grow. In addition to the mechanistically distinct forms of postsynaptic plasticity, presynaptic plasticity offers a powerful means to modify neural cir- cuits. A wide range of induction mechanisms has been identiﬁed, some of which occur entirely in the presynaptic terminal, whereas others require retrograde signaling from the postsynaptic to presynaptic terminals. In spite of this diversity of induction mechanisms, some common induction rules can be identiﬁed across synapses. Although the precise molecular mechanism underlying long-term changes in transmitter release in most cases remains unclear, increasing evidence indicates that presynaptic LTPand LTD can occur in vivo and likely mediate some forms of learning.

t several excitatory and inhibitory synap- synaptic plasticity. Such diversity expands the Ases, neuronal activity can trigger enduring dynamic range and repertoire by which neu- increases or decreases in neurotransmitter re- rons modify their synaptic connections. This release, thereby producing long-term potentiation view discusses mechanistic aspects of presynaptic (LTP) or long-term depression (LTD) of syn- LTP and LTD at both excitatory and inhibitory aptic strength, respectively. In the last decade, synapses in the mammalian brain, with an em- many studies have revealed that these forms phasis on recent ﬁndings. of plasticity are ubiquitously expressed in the mammalian brain, and accumulating evidence indicates that they may underlie behavioral INDUCTION MECHANISMS adaptations occurring in vivo. These studies As illustrated in Figure 1, presynaptic LTP/LT D have also uncovered a wide range of induction at both excitatory and inhibitory synapses can mechanisms, which converge on the presynap- be induced in a homosynaptic or heterosynaptic terminal where an enduring modiﬁcation tic manner, with induction occurring either en- in the neurotransmitter release process takes tirely at the presynaptic terminal or requiring place. Interestingly, presynaptic forms of LTP/ a retrograde messenger arising from the post- LTD can coexist with classical forms of postsynaptic neuron. Each of these four induction

Editors: Morgan Sheng, Bernardo Sabatini, and Thomas Su¨dhof Additional Perspectives on The Synapse available at www.cshperspectives.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a005728 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a005728

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P.E. Castillo

Homosynaptic plasticity Heterosynaptic plasticity

Ca2+ Ca2+

Glu Glu Glu/GABA

Retrograde Glu Glu Retrograde Glu/GABA messenger messenger

Figure 1. Four basic arrangements for presynaptic LTPand LTD. (Top row) Illustrates examples where plasticity is entirely induced presynaptically, either in a homosynaptically (e.g., mossy ﬁber LTP)or heterosynaptically (e.g., associative cortico-lateral amygdala LTP of glutamatergic transmission). (Bottom row) Examples requiring retrograde signaling generated either at the same synapse receiving the signal (left, e.g., eCB-LTD at excitatory synapses) or at a neighboring synapse (right, e.g., eCB-LTD at inhibitory synapses).

mechanisms will be discussed and is summar- eral to CA1 pyramidal cell synapse (Sch-CA1) ized in Table 1. (Nicoll and Malenka 1995). Repetitive activation of MFs with high frequency stimulation (HFS, typically 100 Hz bursts), or naturally oc- Mossy Fiber to CA3 Pyramidal Cell Synapse curring activity patterns (Gundlfinger et al. as a Model for Presynaptic LTP/LTD 2010; Mistry et al. 2010), triggers a long-lasting Arguably, the best characterized form of pre- increase in presynaptic release probability (Pr) synaptic LTP can be found at the mossy fiber and a potentiation of the excitatory synaptic (MF) synapse between dentate gyrus granule response (Nicoll and Schmitz 2005). cells and hippocampal CA3 pyramidal (Ni- Strong evidence indicates MF-LTP results coll and Schmitz 2005). MF-LTP is a prototype from enhanced glutamate release, including for mechanistically similar, presynaptically ex- changes in paired-pulse facilitation, failure rate, pressed, NMDAR-independent and cAMP/ coefficient of variation, miniature EPSC activ- PKA-dependent forms of LTP found in sev- ity, and MK-801 sensitivity (Nicoll and Schmitz eral brain areas including the cerebellum (Sa- 2005). Unlike Sch-CA1 LTP induction, classical lin et al. 1996a), thalamus (Castro-Alamancos presynaptic MF-LTP is NMDAR-independent and Calcagnotto 1999), subiculum (Behr et al. (Harris and Cotman 1986). Evidence indicates 2009), amygdala (Lopez de Armentia and Sah that LTPis induced by an activity-dependent in- 2007), and neocortex (Chen et al. 2009). MF- crease in Ca2þ concentration within MF termi- LTP is mechanistically distinct from classical nals (Zalutsky and Nicoll 1990; Mellor and Ni- NMDAR-dependent LTP at the Schaffer collat- coll 2001) (but see Yeckel et al. 1999). Although

2 Cite this article as Cold Spring Harb Perspect Biol 2012;4:a005728 Downloaded from ieti ril as article this Cite Table 1. Presynaptic long-term plasticity at excitatory and inhibitory synapses in the mammalian brain http://cshperspectives.cshlp.org/ Brain area (species) LTP/LTD Synapse type Induction protocola Induction requirements Referencesb Visual cortex (rat) LTD Excitatory inputs, L5 STDP pairing protocol eCB signaling; postsynaptic Sjo¨strom et al. 2003; Corlew et al. pyramidal cell pairs Ca2þ ; presynaptic NMDAR 2007 odSrn abPrpc Biol Perspect Harb Spring Cold Immature visual LTD Excitatory inputs L4 to TBS eCB signaling; mGluR5 Huang et al. 2008 cortex (mouse) L2/3 neurons Visual cortex LTD GABAergic inputs to L2/3 TBS eCB signaling; mGluR5 Jiang et al. 2010 (mouse, rat) neurons

Visual cortex LTP Excitatory inputs on fast mGluR5 (but not mGluR1), Sarihi et al. 2008 onOctober4,2021-PublishedbyColdSpringHarborLaboratoryPress (mouse) spiking GABAergic postsynaptic calcium, interneurons NMDAR-independent Somatosensory LTD Excitatory inputs to L2/3 STDP pairing protocol eCB signaling, group I mGluR; Bender et al. 2006; Nevian and (barrel) cortex neurons postsynaptic Ca2þ ; Sakmann 2006

2012;4:a005728 (rat) presynaptic NMDAR Sensory-motor LTP Excitatory inputs on TBS NMDAR-independent, Chen et al. 2009 cortex (mouse) somatostatin-expressing postsynaptic calcium- interneurons independent, PKA dependent Somatosensory LTP Pyramidal cell on LTS STDP pairing protocol NMDAR-dependent Lu et al. 2007 cortex (rat) GABAergic interneurons Somatosensory LTD Pyramidal cell on LTS STDP pairing protocol mGluR-dependent, NMDAR/ Lu et al. 2007 cortex (rat) GABAergic interneurons CB1R-independent Prefrontal cortex LTD Excitatory inputs L2/3to Moderate 10 Hz eCB signaling; postsynaptic Lafourcade et al. 2007 (mouse) L5/6 neurons stimulation for 10 min Ca2þ ; mGluR5 rsnpi ogTr Plasticity Long-Term Presynaptic Prefrontal cortex LTD GABAergic inputs to L5/6 Moderate 5 Hz eCB signaling; group I mGluR; Chiu et al. 2010 (rat, mouse) neuorns stimulation for presynaptic D2R 5–10 min Thalamus LTP Cortical inputs to (100 stim, 10 Hz) 6 NMDAR-independent Castro-Alamancos and Calcagnotto (mouse) ventrobasal neurons 1999 Hippocampus LTP Mossy ﬁber to CA3 HFS (25–100 Hz) cAMP/PKA, R-type VGCC, Harris and Cotman 1986; Zalutsky (mouse, rat, pyramidal cell NMDAR-independent and Nicoll 1990; Huang et al. guinea pig) 1994; Weisskopf et al. 1994; Xiang et al. 1994; Yeckel et al. 1999 (see text for additional references)

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Table 1. Continued Brain area (species) LTP/LTD Synapse type Induction protocola Induction requirements Referencesb Dentate (rat) LTP Mossy fiber to dentate 30 Hz bursts paired with PKC-dependent, Alle et al. 2001 gyrus basket cell postsynaptic action PKA-independent, potentials postsynaptic calcium Dentate (rat) LTP Mossy fiber to mossy cells HFS (100 Hz) NMDAR-independent Lysetskiy et al. 2005 Hippocampus LTD Mossy fiber to s.lucidum HFS (100 Hz) Postsynaptic Ca2þ via Maccaferri et al. 1998; Lei and onOctober4,2021-PublishedbyColdSpringHarborLaboratoryPress (mouse, rat) interneurons CP-AMPARs, presynaptic McBain 2004; Pelkey et al. 2005, mGluR7, PKC 2006 Hippocampus LTP Mossy fiber to CA3 HFS (100 Hz) Postsynaptic Ca2þ , L-type Galvan et al. 2008, 2010 (rat) s.lacunosum moleculare VGCC, NMDAR-inde-

ieti ril as article this Cite interneurons pendent, postsynaptic PKA Hippocampus LTP Immature mossy fiber to STDP pairing protocol Postsynaptic Ca2þ ; L-type Sivakumaran et al. 2009 (neonatal rat) CA3 pyramidal cell VGCC; NMDAR- independent; BDNF/trkB; postsynaptic cAMP/PKA Hippocampus LTP Excitatory inputs on CA1 HFS (100 Hz), TBS Postsynaptic Ca2þ via Lamsa et al. 2007; Oren et al. 2009; odSrn abPrpc Biol Perspect Harb Spring Cold (rat) interneurons CP-AMPARs, NMDAR- Nissen et al. 2010 independent Hippocampus LTP Excitatory inputs on CA1 TBS paired with Postsynaptic Ca2þ and Perez et al. 2001; Lapointe et al. 2004; (rat) interneurons postsynaptic mGluR1 activation Topolnik et al. 2006 depolarization Hippocampus LTD Excitatory inputs on CA1 HFS (100 Hz) Retrograde signaling by Gibson et al. 2008 interneurons 12-(S)-HPETE, presynaptic TRPV1, group I mGluR, NMDAR-independent Subiculum LTP CA1-subiculum pyramidal HFS (100 Hz) cAMP/PKA, postsynaptic Kokaia 2000; Wozny et al. 2008a,b 2012;4:a005728 (mouse, rat) cell Ca2þ -independent Hippocampus LTP Schaffer collateral-CA1 HFS (200 Hz) Postsynaptic Ca2þ , L-type Zakharenko et al. 2001; Bayazitov (mouse) pyramidal cell VGCC et al. 2007 Hippocampus LTP Perforant path-CA1 HFS (200 Hz) Postsynaptic NMDARs; L-type, Ahmed and Siegelbaum 2009 (mouse) pyramidal cells T-type VGCCs Downloaded from ieti ril as article this Cite Hippocampus LTD Inhibitory inputs to CA1 HFS, TBS eCB signaling; group I Chevaleyre and Castillo 2003, 2002 http://cshperspectives.cshlp.org/ (rat, mouse) pyramidal cells mGluRs; cAMP/PKA; postsynaptic Ca2þ and NMDAR-independent Cerebellum LTP Parallel fiber to Purkinje 4–10 Hz stimulation cAMP/PKA; NMDAR and Sakurai 1987; Shibuki and Okada (mouse, rat, cell (e.g., 8 Hz, 30 Hz) postsynaptic 1992; Salin et al. 1996b; Storm odSrn abPrpc Biol Perspect Harb Spring Cold guinea pig) Ca2þ -independent et al. 1998; Linden and Ahn 1999; Bender et al. 2009 Cerebellum LTD Parallel fiber to Purkinje 4 Hz, in the presence of eCB signaling NMDAR Qiu and Knopfel 2009 (mouse) cell PKA inhibitor

Cerebellum (rat) LTP Parallel ﬁber to molecular 8 Hz stimulation for 30 s cAMP/PKA Bender et al. 2009; Rancillac and onOctober4,2021-PublishedbyColdSpringHarborLaboratoryPress layer interneuron Crepel 2004 Cerebellum (rat) LTP Parallel ﬁber to stellate cell Pairing protocol: 2 Hz cAMP-independent, Rancillac and Crepel 2004 for 60 s, postsynaptic NO-dependent depolarization 2þ

2012;4:a005728 Cerebellum (rat) LTD Parallel ﬁber to stellate cell 4 25 stim at 30 Hz Postsynaptic Ca ,CP- Soler-Llavina and Sabatini 2006 AMPARs, mGluR1, eCB retrograde signaling, NMDAR-independent Cerebellum LTP Stellate cell-stellate cell HFS (100 Hz) of parallel Presynaptic NMDARs Liu and Lachamp 2006; Lachamp (mouse) ﬁbers et al. 2009 Lateral amygdala LTP Cortico-lateral amygdala Simultaneous repetitive Presynaptic NMDAR, Humeau et al. 2003; Fourcaudot (rat, mouse) neurons stimulation (Poisson cAMP/PKA et al. 2008, 2009 train, 30 Hz average)

of thalamic and cortical Plasticity Long-Term Presynaptic afferents Lateral amygdala LTP Cortico-lateral amygdala Pairing protocol (80 Postsynaptic Ca2þ , NMDAR, Tsvetkov et al. 2002 (rat) neurons stim, 2 Hz) þ30 mV L-type VGCC postsynaptic depolarization Lateral amygdala LTP Thalamic-lateral amygdala HFS (100 Hz) Postsynaptic Ca2þ , presynaptic Huang and Kandel 1998 (rat) neurons cAMP/PKA Lateral amygdala LTP Thalamic-lateral amygdala PP stimulation (50 ms Presynaptic Ca2þ , Shin et al. 2010 (rat) neurons ISI), 2 Hz for 2 min GluK1-containing KAR, NMDAR-independent

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Table 1. Continued Brain area (species) LTP/LTD Synapse type Induction protocola Induction requirements Referencesb Central amygdala LTP Thalamic-central HFS (100 Hz) paired with Presynaptic NMDAR Samson and Pare 2005 (guinea pig) amygdala neurons brief suprathreshold depolarization Central amygdala LTP Nociceptive inputs to HFS (100 Hz) cAMP/PKA; Lopez de Armentia and Sah 2007

(rat) central amygdala NMDAR-independent onOctober4,2021-PublishedbyColdSpringHarborLaboratoryPress neurons Lateral amygdala LTD GABAergic inputs to LFS (1 Hz) eCB signaling; mGluR1; Marsicano et al. 2002; Azad et al. (mouse) lateral amygdala postsynaptic PKA activity 2004 Dorsal striatum LTD Glutamatergic cortical HFS (100 Hz), STDP eCB signaling; group I mGluR; Gerdeman et al. 2002; Kreitzer and 2þ ieti ril as article this Cite (rat, mouse) inputs to medium pairing protocol postsynaptic Ca Malenka 2007; Shen et al. 2008 spiny neurons Nucleus LTD Glutamatergic cortical Moderate 13 Hz eCB signaling; mGluR5; Robbe et al. 2002b accumbens afferents to nucleus stimulation for 10 postsynaptic Ca2þ (mouse) accumbens min Nucleus LTD Cortical afferents to HFS (100 Hz) mGluR2/3, cAMP/PKA Robbe et al. 2002a odSrn abPrpc Biol Perspect Harb Spring Cold accumbens nucleus accumbens signaling (mouse) Ventral tegmental LTD GABAergic inputs to Moderate 10 Hz eCB signaling; group I mGluR, Pan et al. 2008 area (rat) dopamine neurons stimulation for 5 D2R min Ventral tegmental LTP GABAergic inputs to HFS (100 Hz) Postsynaptic Ca2þ ; NMDAR; Nugent et al. 2007 area (rat) dopamine neurons Nitric Oxide/cGMP signaling Dorsal Cochlear LTD Glutamatergic inputs to STDP paring protocol eCB signaling; group I Tzounopoulos et al. 2007 Nucleus Carthwheel GABAergic mGluR-indpependent 2012;4:a005728 (mouse) interneuron aMost typical induction protocol is indicated. Only examples of synaptically induced (i.e., no chemically induced) LTP/LTD in brain tissue are listed. bBecause of space limitations, not all references are listed (see text). Abbreviations: HFS, high frequency stimulation; TBS, theta-burst stimulation; PPF, paired-pulse facilitation; CV, coefﬁcient of variation; STDP, spike timing-dependent plasticity; VGCC, voltage-gated calcium channel, eCB, endocannabinoid; CP, Ca2þ-permeable; D2R, type 2 dopamine receptor; n/a, not available. Downloaded from http://cshperspectives.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press

Presynaptic Long-Term Plasticity

glutamate release at MF-CA3 synapses is me- (Sivakumaran et al. 2009). Given that brain-de- diated by N- and P/Q-type voltage gated Ca2þ rived neurotrophic factor (BDNF)/tyrosine ki- channels (VGCCs), MF-LTP can occur with both nase B (trkB) signaling is also required, BDNF of these channel types blocked (Castillo et al. could act as a retrograde messenger (see below), 1994). In contrast, R-type channels contribute a possibility that needs to be directly tested. An- significantly to MF-LTP,despite playing a minor other mechanism of induction requiring ret- role in overall presynaptic Ca2þ influx and basal rograde signaling has been proposed at mature transmission (Breustedt et al. 2003; Dietrich MF-CA3 synapses. The model involves trans- et al. 2003). Ca2þ influx via R-type VGCCs ap- synaptic interaction between postsynaptic EphB pears to preferentially access presynaptic signals receptor tyrosine kinases and presynaptic B- that trigger MF-LTP, as recently suggested for Ephrin ligands resulting, via an unknown mech- parallel fiber LTP (Myoga and Regehr 2011). anism, in a long-lasting increase in transmitter Pharmacological manipulations and genetic an- release (Contractor et al. 2002; Armstrong et al. alyses using knockout mice indicates that pre- 2006). synaptic Ca2þ activates a Ca2þ/calmodulin-de- MF synapses also express presynaptic LTD. pendent adenylyl cyclase, leading to enhanced Similar protocols of stimulation commonly presynaptic cAMP levels and activation of PKA, used to trigger NMDAR-dependent LTD at Sch- which is necessary for MF-LTP (Huang et al. CA1 synapses also induce a MF-CA3 homosyn- 1994; Weisskopf et al. 1994; Villacres et al. 1998; aptic LTD expressed as a reduction in gluta- Wang et al. 2003). PKA then phosphorylates pre- mate release (Kobayashi et al. 1996). The MF- synaptic substrate(s) to cause a long-lasting in- CA3 synapse is one of few locations where bidi- crease in transmitter release (see below). rectional presynaptic LTP/LTDcan be observed An alternative mechanism for MF-LTP in- in the central nervous system. Presynaptic duction has been proposed. The leading event MF-LTD induction is NMDAR-independent is a postsynaptic Ca2þ enhancement via L-type and seems to require presynaptic mGluR2 as VGCCs and group I mGluR-stimulated release indicated by studies using nonselective mGluR of Ca2þ from internal stores. Ca2þ mobilizes a antagonists and mGluR2 knockout mice (Yokoi retrograde signal in a PKA-dependent manner et al. 1996; Tzounopoulos et al. 1998; Kobayashi (Jaffe and Johnston 1990; Kapur et al. 1998; et al. 1999). Intriguingly, none of these manip- Yeckel et al. 1999). A similar mechanism has re- ulations fully abolishes MF-LTD. Exogenous cently been reported at some MF to CA3 inter- mGluR2 activation is not sufficient for induc- neuron synapses (Galvan et al. 2008, 2010). This tion and must be associated with MF activity, induction model is consistent with Hebbian which presumably provides a Ca2þ-dependent MF-LTP (Urban and Barrionuevo 1996) where- signal (Tzounopoulos et al. 1998; Kobayashi by plasticity is triggered by both presynaptic et al. 1999). Given that Gi/o coupled mGluR2 activity that releases glutamate to activate post- activation leads to decreased cAMP/PKA activ- synaptic group I mGluRs, and postsynaptic de- ity, MF-LTDcould be a reversal of the presynap- polarization to activate L-type VGCCs. Numer- tic process involved in MF-LTP. Unexpectedly, ous studies have not been able to confirm a two recent studies have called into question the postsynaptic model of classical MF-LTP induc- induction mechanism underlying MF-LTD. Us- tion (for a review, see Nicoll and Schmitz 2005), ing more specific and potent group II mGluRs and as a result, no agreement has yet emerged. antagonists, as well as mGluR2/3 double knock- Interestingly, at immature MF-CA3 synapses, out mice, these studies still observed presynaptic which mainly release GABA that acts as excit- MF-LTD (Wostrack and Dietrich 2009; Lyon atory neurotransmitter at early developmental et al. 2011). MF-LTD induced in mGluR2/3 stages, correlated presynaptic and postsynaptic double knockout mice was abolished by phar- activity triggers presynaptically expressed LTP, macologically blocking kainate receptors (Lyon whose induction requires postsynaptic Ca2þ et al. 2011), raising the intriguing possibility rise and postsynaptic cAMP/PKA signaling that these receptors, via a metabotropic action,

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P.E. Castillo

could be involved in the induction of presynap- classical MF-LTP in principal neurons, LTP at tic MF-LTD (Negrete-Diaz et al. 2007). Further MF-basket cell synapses requires PKC but not studies are required to determine the precise PKA activity (Alle et al. 2001). mechanism of presynaptic MF-LTD. Whereas repetitive stimulation triggers pre- Other presynaptic forms of plasticity that synaptic LTP at both MF-mossy cell and MF- are mechanistically similar to MF-LTP have basket cell synapses, a very different picture been identified in multiple brain areas, in- emerges at MF-interneuron synapses (mainly cluding the cerebellum, the amygdala (see Pape MF to s. lucidum interneurons, a.k.a. MF-SLIN and Pare 2010) and subiculum (Table 1) (see synapses) (for a review, see McBain 2008). Re- Behr et al. 2009). In the cerebellum, repetitive markably, the same stimulation paradigm that parallel fiber (PF) stimulation triggers presyn- induces presynaptic LTP in both principal neu- aptic LTP at PF to Purkinje cell synapses. In- rons and mossy cells triggers a NMDAR-induction does not require postsynaptic gluta- dependent form of presynaptic LTD at some mate receptor activation or Ca2þ rises but, as MF-interneuron synapses (Maccaferri et al. for MF-LTP,requires cAMP/PKA signaling (Sa- 1998). These synapses were subsequently iden- kurai 1987; Shibuki and Okada 1992; Salin et al. tified as those expressing Ca2þ-permeable (CP), 1996b; Storm et al. 1998; Linden and Ahn 1999; GluR2-lacking AMPARs (Toth et al. 2000; Lei Bender et al. 2009). Similar presynaptic LTP and McBain 2004). Induction of this form of was subsequently observed at PF to molecular LTD requires a postsynaptic Ca2þ rise via CP- layer interneuron synapses (Rancillac and Cre- AMPARs, and activation of presynaptic mGluR7 pel 2004; Bender et al. 2009). Like MF synapses, receptors, which triggers PKC and a down- PF synapses display bidirectional presynaptic regulation of Ca2þ influx through P/Q-type plasticity. Indeed, PF inputs onto both Purkinje VGCCs to reduce probability of release (Pelkey cells (Qiu and Knopfel 2009) and molecular et al. 2005, 2006). Activation of mGluR7 is nec- layer interneurons (Soler-Llavina and Sabatini essary but not sufficient to induce LTD; post- 2006) can undergo presynaptic LTD. However, synaptic activity and the associated postsynaptic unlike at MF synapses, presynaptic LTD at PF Ca2þ rise are also required to presumably pro- synapses seems to be mediated by endocannabi- mote the mobilization of an as yet unidentified noids (see below). retrograde messenger. Unexpectedly, mGluR7 not only mediates a long-lasting reduction in glutamate release but Presynaptic LTP/LTD at Excitatory also acts as a metaplastic switch such that on Synapses onto Interneurons binding of agonist, mGluR7 is rapidly inter- In addition to CA3 pyramidal cells, MFs estab- nalized and delivery of subsequent HFS then lish synapses with multiple classes of interneu- triggers a de-depression or LTP of synaptic rons, such as excitatory mossy cells in the hillus, transmission (Pelkey et al. 2005). It therefore and inhibitory interneurons in both CA3 and appears that the presence or absence of mGluR7 dentate gyrus. Although HFS of MFs triggers a on the presynaptic surface dictates whether presynaptic form of LTPin mossy cells that is re- the MF-SLIN synapse weakens or strengthens portedly identical to classical MF-LTP in CA3 in response to HFS. The de-depression/LTPun- pyramidal cells (Lysetskiy et al. 2005), a slightly masked by mGluR7 internalization is caused by modified stimulation paradigm applied to pre- an enhancement in glutamate release, the mosynaptic dentate granule cells triggers a form of lecular basis of which will be discussed below. presynaptic LTP at MF–dentate gyrus basket Repetitive activation of MFs can also trigger cells whose induction requires a rise in post- presynaptic LTPon CA3 lacunosum-moleculare synaptic Ca2þ. Because this LTPis expressed pre- interneurons (Galvan et al. 2011). How exactly synaptically, a retrograde messenger is required these multiple forms of synaptic plasticity of (Alle et al. 2001) but the identity of this mes- MFs on interneurons regulate the CA3 network senger remains unknown. Intriguingly, unlike excitability remains to be determined.

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Presynaptic Long-Term Plasticity

Several other examples of presynaptic LTP/ In neocortex (visual and somatosensory LTD have been identified at glutamatergic in- cortices, see Table 1), there is strong evidence puts onto interneurons throughout the brain (Sjo¨strom et al. 2003; Bender et al. 2006; Nevian (Table 1) (for recent, comprehensive reviews and Sakmann 2006; Corlew et al. 2007; Rod- see McBain and Kauer 2009; Kullmann and riguez-Moreno and Paulsen 2008) that pre- Lamsa 2011). As for the examples discussed NMDARs play a key role in the induction of above, induction typically requires postsyn- the LTDcomponent of spike timing-dependent aptic Ca2þ to rise in an NMDAR-independent plasticity (STDP), an associative form of plas- manner. A common source includes Ca2þ in- ticity in which the precise temporal relationship flux via CP-AMPARs, although L-type VGCCs between presynaptic and postsynaptic activity and group I mGluR-stimulated release of Ca2þ determines the direction (t-LTP or t-LTD) and from internal stores may also contribute. What the magnitude of the resulting change in syn- determines the sign of plasticity (i.e., LTP or aptic strength (for a recent review, see Capo- LTD)at a given synapse is unclear but both post- rale and Dan 2008). Induction of preNMDAR- synaptic and presynaptic factors may contribute. dependent t-LTD requires postsynaptic Ca2þ rise and activation of group I mGluRs (at least in somatosensory cortex). In addition, this Presynaptic NMDAR-Dependent Plasticity t-LTDis expressed presynaptically as a long-last- Increasing evidence supports the notion that ing reduction in transmitter release, implicating presynaptic NMDARs (preNMDARs) can reg- a retrograde signal, which has been identified ulate transmitter release and play a key role in as an endogenous cannabinoid (Sjo¨strom et al. the induction of presynaptic forms of plastic- 2003; Bender et al. 2006; Nevian and Sakmann ity (Duguid and Sjostrom 2006; Corlew et al. 2006). As discussed below, endocannabinoids 2008; Rodriguez-Moreno et al. 2010). Physio- (eCB) are well-established retrograde messen- logical studies stronglysuggest that preNMDARs gers mediating most known forms of presynap- can enhance both spontaneous and evoked tic LTDin the brain (Heifets and Castillo 2009). transmitter release (glutamate and GABA) at Because eCBs mediate their effects by targeting some synapses, and there is anatomical evidence presynaptic cannabinoid receptors, an obvious supporting a presynaptic localization (Corlew question is how these receptors interact with et al. 2008). A key experiment in support of NMDARs at the presynaptic terminal to induce preNMDAR-dependent forms of plasticity is t-LTD. PreNMDARs could have an instructive the demonstration that global antagonism of or regulatory role in t-LTD. In the first case, NMDAR blocks induction, whereas blocking given the dual requirement of depolarization postsynaptic NMDARs (e.g., by loading cells and glutamate binding for NMDAR gating, with the NMDAR channel blocker MK-801) preNMDARs act as coincidence detectors of has no effect. Like other presynaptic ionotropic presynaptic action potential-mediated depo- receptors (Engelman and MacDermott 2004), larization and glutamate release. As expected, preNMDARs facilitate transmitter release most t-LTD only occurs if these receptors are acti- likely by direct depolarization of the presynaptic vated within a narrow interval, although presyn- terminal, by permeating Ca2þ, or both. An al- aptic cannabinoid receptors may also contribute ternative mechanism not requiring membrane to set this time window for t-LTD (Sjo¨strom depolarization and Ca2þ influx cannot be dis- et al. 2003; Duguid and Sjostrom 2006). In a carded. Endogenous glutamate that activates regulatory role, preNMDARs somehow facili- preNMDARs can arise from the same terminal tate induction but the coincidence detection (acting as anautoreceptor) orneighboring termi- occurs postsynaptically as a result of group I nals (acting as a heteroreceptor), although post- mGluR activation by glutamate and postsynap- synaptic dendritic release (Duguid and Smart tic Ca2þ rise via L-type VGCCs (Bender et al. 2004) and release from glia could also contrib- 2006; Nevian and Sakmann 2006). In this case, ute (Parpura and Zorec 2010). mGluRs and Ca2þ would act synergistically to

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mobilize eCBs as shown in other systems (Hashi- from stellate cells, presumably by activating pre- motodani et al. 2007). These examples in neo- NMDARs on their terminals (Liu and Lachamp cortex, suggest that the precise interaction of 2006). This heterosynaptic form of LTPalso re- preNMDARs and eCB signaling in setting the quires cAMP/PKA signaling (Lachamp et al. characteristic time window for t-LTDinduction 2009). Finally, in the developing Xenopus reti- is synapse-specific. It will be interesting to know notectal system, light stimuli or theta burst stim- the generality of preNMDAR-dependent t-LTD ulation of the optic nerve triggers presynaptic in other brain areas especially because pre- LTD of GABAergic synaptic transmission on NMDARs expression and subunit composition tectal neurons (Lien et al. 2006). Activation of can be developmentally regulated (Corlew et al. preNMDARs is necessary but not sufficient 2008; Larsen et al. 2011). for induction. Coincident interneuron activity Several studies have shown that activation is also required, and such activity presumably of preNMDARs mediates other forms of pre- provides the required depolarization for presynaptic LTP/LTD at both excitatory and in- NMDAR gating as well as Ca2þ influx through hibitory synapses. Two forms of preNMDAR- presynaptic VGCCs that may also contribute dependent LTP, both expressed presynaptically, to the inhibitory LTD at hippocampal synapses have been reported in the amygdala. In the (Heifets et al. 2008). It remains to be seen lateral amygdala (LA), repeated coincident stim- whether this type of heterosynaptic LTD of ulation of converging cortical and thalamic GABAergic transmission also occurs in the excitatory afferents on LA projection neurons mammalian brain. induces associative LTPat cortical but not thalamic inputs (Humeau et al. 2003). In addition, Retrograde Signaling and Presynaptic induction is independent of postsynaptic activ- LTD/LTP ity, including depolarization, Ca2þ rise and activation of postsynaptic NMDARs, but requires Presynaptic forms of plasticity that include a cAMP/PKA signaling (Fourcaudot et al. 2008). postsynaptic step for their induction also re- A potential mechanism for this heterosynaptic quire some form of retrograde communica- associative form of plasticity is that glutamate tion from the postsynaptic to the presynaptic released by thalamic afferents might directly cell (Fig. 1). Such communication is typically activate preNMDARs on cortical presynaptic mediated by diffusible retrograde messengers, terminals (adding to the homosynaptic acti- substances that are released on activity from vation by glutamate released from these termi- dendrites and the cell body of neurons and, nals), thereby promoting presynaptic Ca2þ in- by targeting the presynaptic terminals, modify crease, which, like for other forms of presyn- transmitter release in a long-lasting manner aptic LTP(e.g., MF-LTP),triggers a long-lasting (Tao and Poo 2001; Regehr et al. 2009). Exten- cAMP/PKA-dependent increase in transmitter sive experimental evidence shows that this release. The other form of preNMDAR-depend- mechanism is involved in several forms of pre- ent LTPin amygdala has been reported at thala- synaptic LTP/LTDat both excitatory and inhib- mic afferents on medial sector neurons in the itory synapses (Table 1). A wide range of retro- central nucleus (Samson and Pare 2005). Unlike grade messengers have been identified in the cortical-LA LTP, LTP in central amygdala is ho- brain, including lipid derivatives, gases, pep- mosynaptic and nonassociative, and much less tides, conventional transmitters (e.g., glutamate is known about its molecular mechanism of in- and GABA), and growth factors (Regehr et al. duction. 2009). Release of retrograde messengers is usu- PreNMDAR-dependent LTP and LTD have ally triggered by postsynaptic Ca2þ rises, but also been reported at GABAergic synapses (Lien Ca2þ-independent release can also occur. De- et al. 2006; Liu et al. 2007). In rodent cerebellar pending on their chemical nature, retrograde cortex, glutamate released from parallel fibers messengers are released in a vesicular or nonve- induces a long-lasting increase of GABA release sicular manner. Although there isgoodagreement

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Presynaptic Long-Term Plasticity

that some of these messengers play an essential The interest in retrograde signaling in pre- role in triggering presynaptic LTP/LTD, the ul- synaptic forms of LTP/LTD has intensified in timate effectors mediating such changes are recent years with the discovery of novel retro- commonly unknown. A much less explored grade messengers as mediators of synaptic mechanism, albeit with potentially great rele- plasticity and the growing recognition of their vance for presynaptic forms of plasticity, in- widespread nature (Alger 2002; Regehr et al. volves adhesion proteins that span the synaptic 2009). In addition, retrograde signaling mediates cleft (Futai et al. 2007; Gottmann 2008). Little is multiple forms of long-term plasticity at inhib- known about this transsynaptic mechanism in itory synapses throughout the brain, certainly LT P /LTD beyond a few examples (Contractor expanding the number of synapse expressing et al. 2002; Armstrong et al. 2006) and it will presynaptic LTP/LTD (Castillo et al. 2011). As not be considered further here. discussed above, there are several forms of pre- The idea that retrograde signaling could me- synaptic LTP/LTD, at both excitatory and inhib- diate long-term synaptic plasticity LTP in par- itory synapses, where the action of a retrograde ticular is not new. This mechanism received a messenger is assumed. Here, presynaptic forms great deal of attention in the early 1990s dur- of LTP/LTD mediated by an identified retro- ing an intense “pre vs. post” debate regarding grade messenger will be briefly discussed. the expression locus of NMDAR-dependent LTP. Several diffusible retrograde messengers Endocannabinoid-Mediated LTD emerged as mediators of this form of plasticity, including arachidonic acid (Williams et al. Endocannabinoids (eCB) mediate one of the 1989), platelet-activating factor (Kato et al. clearest examples of presynaptically expressed 1994), and gases such as carbon monoxide and LTD in the brain (Heifets and Castillo 2009). nitric oxide (NO) (Zhuo et al. 1993, 1994; Son These retrograde messengers are lipids syn- et al. 1996; Hawkins et al. 1998). Not surpris- thesized from membrane precursors, and two ingly, in the field of synaptic plasticity many of of the best characterized eCBs are N-arachido- the studies providing experimental evidence noylethanolamide (anandamide, AEA) and 2- for these messengers also generated a great deal arachidonoylglycerol (2-AG). Neuronal activity of controversy and contradictory results. Tomen- releases eCBs from the postsynaptic compart- tion just one example, NO was strongly im- ment, which travel backward to activate the pre- plicated as being the retrograde messenger me- synaptic type 1 cannabinoid receptor (CB1R, a diating LTP at the Schaffer collateral to CA1 Gi/o protein coupled receptor widely expressed pyramidal cell synapse (for a recent review, see in the brain), thereby suppressing neuro- Feil and Kleppisch 2008). However, subsequent transmitter release at both glutamatergic and studies not only challenged the experimental GABAergic synapses in a transient and a long- evidence, but even the need for a retrograde sig- term manner (Chevaleyre et al. 2006; Kano nal in this form of LTP (for a review on this et al. 2009). Multiple examples of eCB-mediated topic, see Kerchner and Nicoll 2008). It is worth LTD (eCB-LTD) have been identified through- noting that classical NMDAR-dependent LTP is out the mammalian brain (see Table 1) (Heifets not a homogenous phenomenon, and tempo- and Castillo 2009). Although the pattern of af- rally overlapping processes that include a slowly ferent activity may differ between brain regions, developing presynaptic component and rapidly induction of eCB-LTD typically begins with a developing postsynaptic component have been transient increase in activity at glutamatergic identified (Lisman and Raghavachari 2006; Ba- afferents and a concomitant postsynaptic re- yazitov et al. 2007). Although the early post- lease of eCBs from a target neuron. By an unclear synaptically expressed phase may occur in the mechanism that may include an unidentified absence of retrograde signaling, such signaling membrane transporter, eCBs then travel retro- may be important for a late presynaptically ex- gradely across the synaptic cleft to activate pressed LTP (Bayazitov et al. 2007). CB1Rs on the presynaptic terminals of either

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P.E. Castillo

the original glutamatergic afferent (homosyn- hippocampus (Heifets et al. 2008) and dorsal aptic eCB-LTD) or nearby GABAergic afferents striatum (Singla et al. 2007). Together, these (heterosynaptic eCB-LTD) (Chevaleyre et al. observations suggest that Ca2þ influx via pre- 2006). eCB release occurs via two separate post- NMDARs in neocortex, or via presynaptic synaptic processes (Piomelli 2003), activation VGCCs in hippocampus and dorsal striatum, of Gq- protein coupled metabotropic receptors may contribute to the PKA-dependent meta- (typically group I mGluRs and muscarinic ace- bolic process mediating eCB-LTD. In support tylcholine receptors) and depolarization-in- of this possibility is the observation that induced Ca2þ influx via VGCCs. Both pathways duction of eCB-LTD in the hippocampus also contribute to eCB-LTD induction (Heifets and requires the activation of the Ca2þ-sensitive Castillo 2009). The metabotropic pathway en- phosphatase calcineurin, likely shifting the bal- gages phospholipase C (PLC) and diacylglycerol ance of kinase (e.g., PKA) and phophatase ac- lipase (DGL), which produce the eCB 2-AG. tivity in the presynaptic terminal (Heifets et al. Most forms of eCB-LTD require postsynap- 2008). Finally, CB1Rs can interact with other tic Ca2þ increase, which likely facilitates eCB signaling systems to regulate eCB-LTD in- production by activating Ca2þ-dependent en- duction. CB1R and type 2 dopamine receptor zymes, including PLC. Importantly, the metab- (D2R), which share a common signaling path- otropic and Ca2þ-driven mechanisms can act way by inhibiting adenylyl cyclase, act synergis- independently, or synergistically to promote tically to induce eCB-LTD of inhibitory trans- eCB release and eCB-mediated plasticity (Ha- mission in the prefrontal cortex (Chiu et al. shimotodani et al. 2007; Heifets and Castillo 2010) and ventral tegmental area (Pan et al. 2009). 2008). In contrast, BDNF/TrkB signaling, pre- At the presynaptic side, CB1R activation is sumably by inhibiting CB1R function, sup- required for eCB-LTD induction but once presses eCB-LTDinduction at excitatory synap- plasticity is established it becomes CB1R-inde- ses in visual cortex (Huang et al. 2008). These pendent (Chevaleyre and Castillo 2003; Ronesi examples clearly illustrate how multiple interac- et al. 2004). Typically, induction of eCB-LTD tions between modulatory systems can occur at requires that CB1Rs be activated for several mi- the presynaptic terminal to regulate eCB-LTD nutes (Chevaleyre et al. 2006), suggesting that a induction. slow, and probably metabolic process must occur at the presynaptic terminal for eCB-LTD Retrograde Signaling beyond consolidation. Because eCB-LTD requires PKA Endocannabinoids activity (Chevaleyre et al. 2007; Mato et al. 2008), and CB1Rs are negatively coupled to Recent studies have provided additional evi- cAMP/PKA, such process is likely mediated dence in support of previously identified ret- by the ai/o limb of the CB1R G-protein sig- rograde messengers as mediators of unconven- naling cascade. Of note, transient activation of tional forms of presynaptically expressed LTP/ CB1Rs suppresses transmitter release by in- LTD. In the hippocampus, a form of presynaptic hibiting presynaptic VGCCs, an effect likely me- LTDon CA1 interneurons known to require ret- diated by the Gbg limb (Wilson et al. 2001). rograde signaling for induction (McMahon and Another relevant property of eCB-LTD is that Kauer 1997), has recently been reported to be CB1R activation alone may not be sufficient mediated by a derivative of arachidonic acid act- for induction (Heifets and Castillo 2009). In ing on presynaptic TRPV1 channels (Gibson neocortex, using spike timing-dependent pro- et al. 2008). This form of plasticity is triggered tocols of induction, it has been shown that by HFS of Schaffer collaterals, the same induc- coincident activation of preNMDARs is also tion protocol typically used to trigger LTP at required (Sjo¨strom et al. 2003; Bender et al. Sch-CA1 synapses. Activation of postsynaptic 2006; Nevian and Sakmann 2006). Presynaptic group I mGluRs by glutamate released during activity is also necessary for induction in the tetanus generates arachidonic acid, which is

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rapidly converted to 12-(S)-HPETE by 12-lip- aforementioned studies used preparations in oxygenase. 12-(S)-HPETE is a membrane-per- earlystages of development. Whether BDNF ret- meable lipid with a short half-life that travels rograde signaling could also mediate presyn- retrogradely across the synapse, in which it aptic plasticity in older animals remains un- activates TRPV1 receptors on presynaptic gluta- known. matergic nerve terminals. Activation of TRPV1 NO can also act as retrograde messenger to receptors is necessary and sufficient for the persistently increase GABA release onto dopa- induction of this form of LTD. The precise minergic neurons in the ventral tegmental area mechanism by which TRPV1 triggers a long- (Nugent et al. 2007, 2009), a brain region cru- lasting reduction of glutamate release remains cial for reward processing and drug addiction. unknown but it has been speculated that Ca2þ As for eCB-LTD at inhibitory synapses, this entry through the TRPV1 channel could acti- form of inhibitory LTP is heterosynaptic as it vate a signaling cascade responsible for LTD(Gib- is triggered by HFS of glutamatergic fibers. In son et al. 2008). A similar form of TRPV1-de- this case, induction requires NMDAR activa- pendent LTD has recently been reported in the tion, postsynaptic Ca2þ rise, NO release from developing superior colliculus (Maione et al. the dopaminergic cell and cGMP signaling in 2009). It is worth noting that 12-(S)-HPETE the GABAergic terminal. How exactly cGMP has also been implicated in mGluR-dependent persistently increases GABA release remains un- LTD at hippocampal Sch CA1 synapses (Fein- known. Interestingly, a single in vivo exposure mark et al. 2003), a form of plasticity with a pre- to morphine abolishes inhibitory LTPin ventral synaptic component of expression (Bolshakov tegmental slices 24 hours later (Nugent et al. and Siegelbaum 1994; Oliet et al. 1997; Zakhar- 2007), an observation consistent with the no- enko et al. 2002). The potential 12-(S)-HPETE tion that exposure to addictive drugs can alter target(s) that mediate this form of LTD are also synaptic plasticity in the brain reward pathway unknown. (Kauer and Malenka 2007). Of note, both LTP Neurotrophins such as brain-derived neu- (Nugent et al. 2007) and LTD (Pan et al. 2008) rotrophic factor (BDNF) have been shown to of inhibitory transmission may be induced in modulate both excitatory and inhibitory trans- the ventral tegmental area. Although the re- mission (Lessmann et al. 2003; Lu 2003; Blum quirements for induction differ, both types are and Konnerth 2005). There is also evidence expressed presynaptically. Finally, an activity- that BDNF can be secreted from dendritic com- dependent, long-lasting increase in GABA re- partments in response to neuronal activity to lease via NO retrograde signaling has recently act as a retrograde messenger and regulate trans- been reported in the thalamus (Bright and mitter release (Du and Poo 2004; Magby et al. Brickley 2008), raising the possibility that a 2006; Kuczewski et al. 2010). Recent studies similar form of NO-dependent LTP of GABA- have provided evidence for a retrograde action ergic transmission may occur in other brain of dendritically released BDNF to potentiate areas. GABAergic release in the visual cortex (Inagaki et al. 2008), hippocampus (Gubellini et al. 2005; Modulatory Role of Presynaptic Receptors Sivakumaran et al. 2009) and optic tectum (Liu et al. 2007). Although the induction proto- By regulating Ca2þ influx or some metabolic cols vary between brain regions, a postsynaptic step downstream of Ca2þ influx, both ionotro- Ca2þ rise is invariably required, which presum- pic and metabotropic receptors at presynaptic ably enables BDNF secretion (Lessmann et al. terminals can modulate the inducibility of pre- 2003). Although the long-lasting enhancement synaptic LTP/LTD. Such modulation has been of GABA release likely results from the activa- reported at several synapses expressing diverse tion of presynaptic TrkB receptors by BDNF, forms of presynaptic plasticity. Once again, a how exactly TrkB/BDNF signaling enhances good example can be found at the MF-CA3 syn- transmitter release is unknown. Notably, the apse where both suppression and facilitation of

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plasticity has been reported. For example, acti- sion along dendrites, thereby imposing spatial vation of presynaptic GABAB and k opioid re- constrains to the synaptically-driven produc- ceptors by endogenously-released GABA and tion of eCBs that mediate LTD at parallel fiber dynorphin, respectively, increases the induction to stellate cell neurons synapses (Soler-Llavina threshold for MF-LTP (Weisskopf et al. 1993; and Sabatini 2006). Vogt and Nicoll 1999). In addition, presumably Associativity has also been observed at the by activating presynaptic A1 receptors, adeno- level of the retrograde signal production in sine can also depress MF-LTP induction (Alz- which two coincident signals are required (Ben- heimer et al. 1991; see also Moore et al. 2003). der et al. 2006; Nevian and Sakmann 2006). PLC Activation of presynaptic type II mGluRs by is likely the coincident detector, integrating glu- synaptically-released glutamate does not seem tamate release via group I mGluR activation and to regulate MF-LTP induction (Vogt and Nicoll activity-driven postsynaptic Ca2þ rise (Hashi- 1999) but can depotentiate MF-LTPimmediately motodani et al. 2007). Endogenous muscarinic after induction (Tzounopoulos et al. 1998; Chen acetylcholine receptor activation also acts as an et al. 2001). In contrast to these suppressive ef- associative signal for eCB-LTD induction in the fects, several studies have shown that induction dorsal cochlear nucleus (Zhao and Tzounopou- of MF-LTPcan be facilitated by presynaptic kai- los 2011). These few examples illustrate how nate receptors (KARs) (for a recent review, see associativity is not an exclusive property of Contractor et al. 2011). How exactly presynaptic postsynaptic LTP/LT D. KARs facilitate MF-LTP remains to be elucidated. EXPRESSION MECHANISMS What changes take place at the presynaptic ter- Input-Specificity and Associativity in minal to account for the long-lasting increase Presynaptic LTP and LTD or decrease in transmitter release associated Like postsynaptic LTP/LTD, presynaptic LTP/ with presynaptic forms of LTP or LTD? Inten- LTD shows input-specificity and associativity, sive work in this area has shown that answering two properties making activity-dependent syn- this question is much harder than originally aptic plasticity a good cellular model of learn- thought. An important constraint in presynap- ing. In cases requiring a retrograde messenger, tic plasticity studies is the relatively small size of the signal may diffuse and target unrelated syn- most typical presynaptic terminals in the CNS, apses, thereby compromising input-specificity making their accessibility for biochemical/ and degrading information processing. How- molecular manipulations, and both long-term ever, this theoretical possibility has not been live imaging and electrophysiological record- supported experimentally. One way to ensure ings extremely difficult. Transmitter release is input-specificity is by combining retrograde a particularly complex phenomenon that in- signaling with presynaptic activity. This dual volves several steps and molecular players (Su¨d- requirement has been shown for eCB-LTD in hof 2004; Pang and Sudhof 2010), allowing for visual cortex (Sjo¨strom et al. 2003), dorsal stria- multiple points of regulation (Atwood and Ka- tum (Singla et al. 2007), and hippocampus runanithi 2002; Catterall and Few 2008; de Jong (Heifets et al. 2008). Similar requirements are and Verhage 2009). Changes in transmitter re- observed for heterosynaptic associative LTP at lease at central synapses can occur as a result cortico-lateral amygdala synapses, except that of modifications in the probability of release in this case, the signal is glutamate arising (Pr) and the number of functional release sites. from neighboring thalamic terminals (Humeau In turn, Pr is determined by several factors; et al. 2003). An additional mechanism underly- including the amount of Ca2þ influx through ing input-specificity can be found in cerebellar presynaptic VGCCs, the distance between these stellate cell neurons in which functional den- channels and the Ca2þ sensor for vesicle release, dritic compartments preclude calcium diffu- presynaptic Ca2þ dynamics, functional state,

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number and precise localization of synaptic Ca2þ imaging from anatomically defined MF vesicles. Transmitter release can occur in a uni- terminals and selective VGCC blockers, this vesicular or multivesicular manner, and the form of LTD has been shown to be associated magnitude of the multivesicular release compo- with a long-lasting depression of the presyn- nent can be altered during presynaptic plasticity aptic Ca2þ transient, which arises through a (Bender et al. 2009). In addition to changes in preferential depression of P/Q-type VGCCs Pr, “presynaptic unsilencing” (Voronin 1994; and is blocked by an mGluR7 antagonist (Pelkey Kerchner and Nicoll 2008) could also contrib- et al. 2006). How exactly mGluR7 activation ute to plasticity. Indeed, studies using dentate produces irreversible depression of P/Q-type granule cell autapses (Tong et al. 1996) and op- VGCCs remains unknown but it could involve tical imaging of postsynaptic Ca2þ transients in PKC-dependent modulation of these channels slice culture (Reid et al. 2004) have shown that (Perroy et al. 2000; Pelkey et al. 2005). A similar recruitment of new release sites could partici- mechanism of expression mediated by presyn- pate in MF-LTP. While in theory any of these aptic P/Q-type VGCCs has been reported in mechanisms could be involved in presynaptic the nucleus accumbens. In this structure, two forms LTP and LTD, most evidence points to forms of presynaptic LTD at excitatory corti- two key points of regulation—presynaptic ac- cal inputs coexist (Table 1); one is induced by tion potential-induced Ca2þ influx and the HFS and requires activation of presynaptic downstream release machinery (Fig. 2). mGluR2/3 (Robbe et al. 2002a), whereas the other is triggered by moderate repetitive stimulation and requires activation of presynaptic Changes in Presynaptic Calcium CB1R (Robbe et al. 2002b; Mato et al. 2008). Ca2þ ions play a crucial role in neurotrans- Both forms of LTD depend on cAMP/PKA sig- mission. Ca2þ influx via VGCCs triggers neuro- naling consistent with the fact that mGluR2/3 transmitter release, and multiple mechanisms and CB1R are Gi/o protein-coupled receptors. can regulate presynaptic VGCCs function (Cat- Remarkably, blockade of P/Q-type, but not terall and Few 2008; Neher and Sakaba 2008). of L- or N-type, VGCCs occludes both forms There is evidence that some forms of presynap- of LTD (Robbe et al. 2002a; Mato et al. 2008), tic LTP/LTD involve enduring changes in pre- which also mutually occlude (Mato et al. 2005), synaptic Ca2þ influx. The best example can be suggesting that mGluR2/3-LTD and eCB-LTD found in the hippocampal mGluR7-dependent share a common mechanism. LTD at MF synapses on s. lucidum interneuron Two recent studies suggest that long-lasting (MF-SLIN LTD, see above). Using two-photon changes in presynaptic Ca2þ influx also underlie

MF-SLIN MF-CA3 Inhibitory LTD LTP eCB-LTD

AC AC Ca2+ mGluR7 + CB1R – cAMP PKC cAMP R α VGCC PKA CaN PKA – P – + + P Rim1α Rim1α ?? P/Q P/Q P/Q VGCC VGCC Ca2+ VGCC Glu Ca2+ Glu Ca2+ GABA

Figure 2. Expression mechanisms of presynaptic LTPand LTD: three prototypical examples (see text).

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P.E. Castillo

presynaptic forms of LTP,but in this case L-type Changes in the Release Machinery and N-type VGCCs seem to be involved. In- deed, using electrophysiological recordings and The other major mechanism for regulating neu- two-photon imaging of FM1-43 dye uptake rotransmitter release is via modulation of the and release at presynaptic terminals, one study molecular machinery responsible for synaptic showed that LTP at perforant path synapses in vesicle exocytosis. Given the large number of CA1 is associated with an enduring increase proteins involved in this complex process, sev- in the contribution of N-type VGCCs to trans- eral candidate proteins could potentially me- mitter release (Ahmed and Siegelbaum 2009). diate long-term synaptic plasticity, and some In contrast, the other study reported that pre- of them have been directly tested mainly using synaptic expression of associative LTP in lateral gene knockout approaches. One way to mod- amygdala is caused by a persistent increase ulate function of these proteins is by protein in L-type VGCC-mediated glutamate release phosphorylation (Leenders and Sheng 2005; de (Fourcaudot et al. 2009), which is an intrigu- Jong and Verhage 2009). Because of the key ing observation given that presynaptic Ca2þ in- role of cAMP/PKA signaling in multiple forms flux at most synapses is mainly mediated by of presynaptic LTP and LTD (see above), most N-type and P/Q-type VGCCs, but not L-type attention has been directed to presynaptic pro- VGCCs. Future studies are required to deter- teins known to be substrates for PKA (Seino and mine the role of VGCCs in the expression of Shibasaki 2005). Among these proteins, synap- other forms or presynaptic LTP. sins (Spillane et al. 1995), rabphilin (Schlu¨ter A potential role of presynaptic Ca2þ influx et al. 1999) and tomosyn (Sakisaka et al. 2008) in presynaptic LTP was also examined in the have been shown to play no role in presynaptic hippocampus at the MF-CA3 synapse. Using MF-LTP. In contrast, the active zone protein direct imaging of the action potential-depen- RIM1a has emerged as a key player not only dent presynaptic Ca2þ transient in MF bou- in MF-LTP but also several others forms of pre- tons, several studies have consistently shown synaptic plasticity (Kaeser and Sudhof 2005). that no change in presynaptic Ca2þ occurs fol- Interestingly, deletion of RIM1a is associated lowing MF-LTP(Regehr and Tank1991; Kamiya with significant cognitive deficits (Powell et al. et al. 2002; Reid et al. 2004). Similarly, no 2004). RIM1a is a large multidomain protein changes in Ca2þ transients were observed in that forms a scaffold at the presynaptic active the cerebellum following cAMP-mediated po- zone and interacts with multiple presynaptic tentiation of parallel fiber to Purkinje cell syn- proteins. As a result, RIM1a is in a strategic po- aptic transmission (Chen and Regehr 1997), a sition to modulate transmitter release (Kou- chemical form of plasticity that mimics synapti- shika et al. 2001; Schoch et al. 2002). Indeed, cally-induced PF-LTP (Salin et al. 1996a). To- RIM1a has been shown to be necessary for gether, these studies show that the long-lasting several cAMP/PKA-dependent forms of pre- enhancement of transmitter release, at least at synaptic plasticity including, MF-LTP (Castillo these synapses, must occur downstream from et al. 2002), cerebellar PF-LTP (Castillo et al. Ca2þ entry. 2002), MF-SLIN LTP or de-depression (Pelkey Finally, indirect changes in Ca2þ entry et al. 2008), associative LTP in lateral amygdala through VGCCs can occur as a result of modifi- (Fourcaudot et al. 2008), late LTP at Sch-CA1 cations in the presynaptic action potential wave- synapses (Huang et al. 2005), GABAergic LTP form. Although modulations in the excitability at stellate cells in cerebellum (Lachamp et al. of the presynaptic terminal as a mechanism of 2009), and inhibitory eCB-LTD in the hippo- synaptic plasticity have been well documented campus and amygdala (Chevaleyre et al. 2007). in invertebrates (for a recent review, see Glanz- In addition, RIM1a is a putative effector for man 2010), the evidence for such a mechanism the synaptic vesicle protein Rab3A, a protein underlying presynaptic LTP or LTD in verte- essential for MF-LTP (Castillo et al. 1997), MF- brates is rather scarce. LTD (Tzounopoulos et al. 1998), and late-LTP

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in CA1 (Huang et al. 2005). The mechanism main to be elucidated. Chief among them is emerging from these studies is that increases the precise molecular pathways underlying pre- of PKA activity and RIM1a phosphorylation synaptic plasticity. Although some key “players” leads to LTP, whereas a reduction of PKA ac- have been identified, there are several loose tivity, in conjunction with phosphatase acti- ends. Presynaptic and postsynaptic LTP/LT D vity, dephosphorylates RIM1a, which results can coexist, and often times their induction dif- in LTD. However, recent studies have challenged fers, but in some cases overlap. It is unclear how this simplistic model by demonstrating that these different forms of plasticity interact and mutation of serine-413, the RIM1a phosphor- how they contribute to information processing. ylation site by PKA that has reported to be nec- The retrograde signal involved in the in- essary for presynaptic LTP in parallel fiber syn- duction of multiple forms of presynaptic LTP/ apses formed in vitro by cultured cerebellar LTD needs to be identified. Although most neurons (Lonart et al. 2003), had no effect on studies focused on presynaptic LTP/LTDinduc- MF-LTP, PF-LTP and eCB-LTD at inhibitory tion and expression, much less is known about synapses (Kaeser et al. 2008; Yang and Calakos the maintenance and reversibility. Moreover, 2010). This observation is consistent with the protein synthesis seems to be required for pre- fact that the presynaptic enhancement of syn- synaptic plasticity at the MF-CA3 synapse aptic transmission following transient activa- (Huang et al. 1994; Calixto et al. 2003; Barnes tion of adenylyl cyclase is unaltered in knockout et al. 2010) and in the dorsal striatum (Yin mice lacking Rab3A or Rim1a (Castillo et al. et al. 2006), and there is evidence that protein 1997, 2002). Together, these findings argue synthesis can occur in the presynaptic compart- that, although the RIM1a complex is essential ment (Giuditta et al. 2002; Yin et al. 2006; for presynaptic long-term plasticity, PKA regu- Barnes et al. 2010). The role of the newly synthe- lates this type of plasticity by a mechanism dis- sized proteins and their potential contribution tinct from RIM1a phosphorylation at serine to putative structural changes in presynaptic 413. In fact, PKA-dependent modulation of plasticity remains largely unexplored. Other fu- transmitter release can occur as a result of the ture research areas include the potential con- phosphorylation/ dephosphorylation of several tribution of glia, interactions between various other presynaptic proteins involved in exo- modulatory systems and metaplasticity of pre- cytosis (Seino and Shibasaki 2005; de Jong synaptic LTP/LT D. and Verhage 2009). Future studies are necessary Perhaps the most difficult challenge ahead to identify the nature of such a presynaptic pro- is to understand how presynaptic long-term tein(s) in PKA-dependent and RIM1a-depen- plasticity contributes to behavior. Accumulat- dent forms of plasticity. Remarkably, not all ing evidence strongly suggest that presynaptic forms of presynaptic LTP/LTD require cAMP/ forms of plasticity can underlie some forms of PKA signaling, and as a result, the number of learning. A good example can be found in the candidate presynaptic proteins putatively in- amygdala where presynaptic LTP and LTD are volved in synaptic plasticity may be larger than known to contribute to fear memory (Maren expected. 2005; Sigurdsson et al. 2007; Sah et al. 2008; Pape and Pare 2010). The link between plasticity and behavior in other brain areas is assumed CONCLUSIONS, CHALLENGES, AND and more difficult to show. Synaptic plasticity FUTURE DIRECTIONS is typically studied in brain slices, often times More than two decades of research unequivo- using relatively nonphysiological induction pro- cally showed that long-term presynaptic plas- tocols and recording conditions. Although an ticity at excitatory and inhibitory synapses is extremely powerful experimental model to ad- widely used throughout the brain. Although dress mechanistic questions, the concepts devel- some learning rules for presynaptic LTP and oped from slice physiology need to be tested in LTD are now understood, many questions re- intact animal preparations to fully understand

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P.E. Castillo

the contribution of presynaptic forms of plas- Bender VA, Pugh JR, Jahr CE. 2009. Presynaptically ex- ticity to behavior. pressed long-term potentiation increases multivesicular release at parallel fiber synapses. J Neurosci 29: 10974– 10978. Blum R, Konnerth A. 2005. Neurotrophin-mediated rapid ACKNOWLEDGMENTS signaling in the central nervous system: Mechanisms and functions. Physiology (Bethesda) 20: 70–78. Special thanks to Thomas Younts and Sachin Bolshakov VY,Siegelbaum SA. 1994. Postsynaptic induction Makani for critical reading of the manuscript. and presynaptic expression of hippocampal long-term The author apologizes to all the investigators depression. Science 264: 1148–1152. whose work could not be cited owing to space Breustedt J, Vogt KE, Miller RJ, Nicoll RA, Schmitz D. 2003. a1E-containing Ca2þ channels are involved in synaptic limitations. P.E.C is supported by the National plasticity. Proc Natl Acad Sci 100: 12450–12455. 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P.E. Castillo

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Presynaptic LTP and LTD of Excitatory and Inhibitory Synapses

Pablo E. Castillo

Cold Spring Harb Perspect Biol 2012; doi: 10.1101/cshperspect.a005728 originally published online December 6, 2011

Subject Collection The Synapse

Studying Signal Transduction in Single Dendritic Synaptic Vesicle Endocytosis Spines Yasunori Saheki and Pietro De Camilli Ryohei Yasuda Synaptic Vesicle Pools and Dynamics Short-Term Presynaptic Plasticity AbdulRasheed A. Alabi and Richard W. Tsien Wade G. Regehr Synapses and Memory Storage NMDA Receptor-Dependent Long-Term Mark Mayford, Steven A. Siegelbaum and Eric R. Potentiation and Long-Term Depression Kandel (LTP/LTD) Christian Lüscher and Robert C. Malenka Synapses and Alzheimer's Disease Ultrastructure of Synapses in the Mammalian Morgan Sheng, Bernardo L. Sabatini and Thomas Brain C. Südhof Kristen M. Harris and Richard J. Weinberg Synaptic Cell Adhesion Calcium Signaling in Dendritic Spines Markus Missler, Thomas C. Südhof and Thomas Michael J. Higley and Bernardo L. Sabatini Biederer Synaptic Dysfunction in Neurodevelopmental Synaptic Neurotransmitter-Gated Receptors Disorders Associated with Autism and Intellectual Trevor G. Smart and Pierre Paoletti Disabilities Huda Y. Zoghbi and Mark F. Bear The Postsynaptic Organization of Synapses Synaptic Vesicle Exocytosis Morgan Sheng and Eunjoon Kim Thomas C. Südhof and Josep Rizo Presynaptic LTP and LTD of Excitatory and Vesicular and Plasma Membrane Transporters for Inhibitory Synapses Neurotransmitters Pablo E. Castillo Randy D. Blakely and Robert H. Edwards

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