Homeostatic Signaling and the Stabilization of Neural Function

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Graeme W. Davis1,* 1Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2013.09.044

The brain is astonishing in its complexity and capacity for change. This has fascinated scientists for more than a century, filling the pages of this journal for the past 25 years. But a paradigm shift is underway. It seems likely that the plasticity that drives our ability to learn and remember can only be meaningful in the context of otherwise stable, reproducible, and predictable baseline neural function. Without the existence of potent mechanisms that stabilize neural function, our capacity to learn and remember would be lost in the chaos of daily experiential change. This underscores two great mysteries in neuroscience. How are the functional properties of individual neurons and neural circuits stably maintained throughout life? And, in the face of potent stabilizing mechanisms, how can neural circuitry be modified during neural development, learning, and memory? Answers are emerging in the rapidly developing field of homeostatic plasticity.

Introduction intrinsic firing properties that were characteristic of that cell It has become clear that homeostatic signaling systems act in vivo. The effect was shown to be both activity and calcium throughout the central and peripheral nervous systems to stabi- dependent. This phenomenon has now been extended to the lize the active properties of nerve and muscle (Davis, 2006; function of entire neural circuits in both invertebrates (Haedo Marder, 2011; Turrigiano, 2011). Evidence for this has accumu- and Golowasch, 2006; see Figure 2) and the developing verte- lated by measuring how nerve and muscle respond to the persis- brate spinal cord (Gonzalez-Islas and Wenner, 2006). tent disruption of synaptic transmission, ion channel function, or A related phenomenon has been revealed in animals harboring neuronal firing. In systems ranging from Drosophila to human, mutations in genes that encode ion channels. Several studies cells have been shown to restore baseline function in the provide evidence that deleting an ion channel gene invokes continued presence of these perturbations by rebalancing ion compensatory changes in the expression of other ion channels channel expression, modifying neurotransmitter receptor traf- in both invertebrate and mammalian systems (MacLean et al., ficking, and modulating neurotransmitter release (Frank, 2013; 2003; Swensen and Bean, 2005; Muraro et al., 2008; Andra´ sfalvy Maffei and Fontanini, 2009; Watt and Desai, 2010). In each et al., 2008; Nerbonne et al., 2008; Van Wart and Matthews, example, if baseline function is restored in the continued pres- 2006; Bergquist et al., 2010). In many cases, ion channel expres- ence of a perturbation, then the underlying signaling systems sion is rebalanced and cell-type-specific firing properties are are considered homeostatic (Figure 1). restored (Figure 2). One conclusion is that homeostatic signaling This is a rapidly growing field of investigation that can be sub- systems enable a neuron to compensate for the absence of an divided into three areas that are defined by the way in which a ionic current and re-establish cell-type-specific firing properties cell responds to activity perturbation, including the homeostatic through altered expression of other ion channels. A second control of intrinsic excitability, neurotransmitter receptor expres- conclusion is that ion channel expression is not a fixed param- sion, and presynaptic neurotransmitter release. Each area is eter associated with cell fate. Rather, a given cell type can main- introduced below. An exciting prospect is that the logic of tain characteristic firing properties using different combinations homeostatic signaling systems, if not specific molecular path- of ion channel densities. The homeostatic rebalancing of ways, will be evolutionarily conserved. The nervous systems of ion channel expression is astonishing, in part, because of its all organisms confront perturbations ranging from genetic and staggering complexity (Marder and Prinz, 2002). There can be developmental errors to changing environmental conditions. In thousands of synaptic inputs and dozens of different channels this relatively short Perspective, it is not possible to achieve a controlling the firing properties of an individual cell. The molecu- comprehensive description of the molecular advances in each lar mechanisms that achieve the homeostatic rebalancing of ion system. Rather, an attempt is made to draw parallels across channel expression remain virtually unknown (but see Muraro systems where conserved processes are emerging. et al., 2008; Driscoll et al., 2013; Temporal et al., 2012; Khorkova and Golowasch, 2007). The Homeostatic Control of Intrinsic Excitability The homeostatic control of intrinsic excitability was brought to Homeostatic Control of Synaptic Efficacy: Synaptic the forefront by experiments that followed the fate of a neuron Scaling at the Postsynaptic Density that was removed from its circuit and placed in isolated cell cul- Synaptic scaling was revealed by experiments examining the ture (Turrigiano et al., 1994). Over a period of days, the isolated effects of chronic activity suppression in cultured mammalian neuron rebalanced ion channel surface expression and restored neurons (Turrigiano et al., 1998; O’Brien et al., 1998). It is now

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2008) can be sufficient to induce synaptic scaling (Figure 3). Even more remarkable is evidence that synaptic scaling can be input specific (Deeg and Aizenman, 2011) and even synapse specific (Be´ ı¨que et al., 2011) when the manipulation of neural activity is restricted to subsets of inputs contacting a given postsynaptic neuron (Figure 3). It is not yet clear whether the magnitude of the scaling response is matched to the magnitude of the perturbation. This is impossible to determine in experiments using tetrodotoxin (TTX) to block neural activity. In experiments in which neural activity is modulated, synaptic scaling participates in the restoration of baseline firing properties in vivo (Keck et al., 2013; Hengen et al., 2013). However, synaptic scaling is often observed to act in concert with other compensatory changes including changes in presynaptic neurotransmitter release (Burrone et al., 2002; Kim and Tsien, 2008; Lu et al., 2013) or intrinsic excitability (Lambo and Turrigiano, 2013). It remains entirely unknown how multiple homeostatic effectors are coordinated to restore cell-type-specific firing properties.

Homeostatic Control of Presynaptic Neurotransmitter Release Figure 1. Evidence for the Homeostatic Control of Cellular Excitation The homeostatic modulation of presynaptic neurotransmitter Top: the firing properties of central neurons are determined by a balance of release was brought to the forefront through studies at the synaptic excitation (red vesicles and red receptors), synaptic inhibition (blue genetically tractable Drosophila neuromuscular junction (NMJ; vesicles and blue receptors), and the densities of ion channels that either mediate cellular depolarization (red ovals) or oppose cellular depolarization Davis and Goodman, 1998a). Genetic manipulations that alter (blue ovals). In response to chronic suppression of neural activity, central postsynaptic glutamate receptor function (Petersen et al., neurons can alter the relative abundance of ion channels and receptors at the 1997; Davis et al., 1997; Frank et al., 2006), muscle innervation cell surface to re-establish a set point level of activity. Bottom: at the neuro- (Davis and Goodman, 1998b), or muscle excitability (Paradis muscular junction (NMJ), chronic impairment of postsynaptic neurotransmitter receptor sensitivity or receptor abundance leads to a compensatory increase et al., 2001) were shown to induce large compensatory changes in presynaptic neurotransmitter release that precisely counteracts the change in presynaptic neurotransmitter release that precisely restore set in receptor function to achieve normal synaptic depolarization of the muscle. point muscle depolarization in response to nerve stimulation. Modified from Davis (2006). This phenomenon has been referred to as ‘‘synaptic homeostasis’’ but will be referred to here as ‘‘presynaptic homeostasis.’’ clear, both in vitro and in vivo, that chronic manipulation of neural This form of homeostatic signaling is evolutionarily conserved activity drives counteracting changes in neurotransmitter recep- from fly to human at the NMJ (Cull-Candy et al., 1980; Plomp tor abundance that help to restore neural activity to baseline et al., 1992). As with other forms of homeostatic plasticity, levels (Thiagarajan et al., 2005; Zhao et al., 2011; Garcia-Bere- this is a quantitatively accurate form of neuromodulation guiain et al., 2013; Mrsic-Flogel et al., 2007; Echegoyen et al., (Figure 2B; Frank et al., 2006). It can be induced in seconds to 2007; Deeg and Aizenman, 2011; Gainey et al., 2009; Keck minutes, during which its expression is independent of transcrip- et al., 2013; Hengen et al., 2013; see also Tyagarajan and Frit- tion or translation (Frank et al., 2006). It can also be stably schy, 2010). The bidirectional modulation of neurotransmitter maintained, a process that requires transcription (Marie et al., receptor abundance was initially termed ‘‘synaptic scaling’’ 2010). Presynaptic homeostasis at the NMJ is bidirectional and because the measured amplitudes of spontaneous miniature can be synapse specific (Davis and Goodman, 1998b; Daniels release events are modified in a multiplicative manner, presum- et al., 2006). ably through proportional changes in receptor abundance at Importantly, presynaptic homeostasis has also been observed every individual synapse (Turrigiano et al., 1998; Turrigiano, at mammalian central synapses in vitro in response to differ- 2011; see also Kim and Tsien, 2008). This effect has the property ences in target innervation (Liu and Tsien, 1995), altered post- of preserving the relative differences in efficacy among the synaptic excitability (Burrone et al., 2002; Thiagarajan et al., numerous synapses on a single postsynaptic target. Because 2005; but see Goold and Nicoll, 2010; Deeg and Aizenman, of this, it has been proposed that synaptic scaling stabilizes 2011), and after chronic inhibition of neural activity (Kim and neuronal excitability while preserving learning-related informa- Ryan, 2010; Zhao et al., 2011). Regardless of the system being tion contained in relative synaptic weights. Synaptic scaling studied, the expression of presynaptic homeostasis is remark- can be induced over the course of hours to days (Turrigiano, able because it involves the rapid, persistent, and accurate mod- 2011). It requires transcription and in some cases may be ulation of presynaptic vesicle fusion. achieved through local protein translation (Sutton et al., 2006, 2007). Synaptic scaling is generally studied in response to alter- Homeostatic Design ations in global neural activity. However, manipulating the activ- The homeostatic modulation of neural function is distinct from ity of individual neurons (Goold and Nicoll, 2010; Ibata et al., other forms of neural plasticity because it is a quantitatively

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accurate form of modulation. For example, the homeostatic rebalancing of ion channel expression precisely counteracts the loss of the Kv4.2 potassium channel in pyramidal neurons and achieves firing properties that are almost indistinguishable from controls (Figure 2A). It should be pointed out, however, that compensation is not perfect because it is constrained by the unique subcellular localization and functional properties of the compensating ion channels (see also Bergquist et al., 2010). In Kv4.2 knockout pyramidal neurons, somatic excitability is precisely restored but dendrites remain hyperexcited (Chen et al., 2006; Nerbonne et al., 2008; see also Van Wart and Mat- thews, 2006). Another example of quantitative accuracy is found at the NMJ. The magnitude of postsynaptic glutamate receptor inhibition is accurately offset, over a wide range, by a graded increase in presynaptic neurotransmitter release (Figure 2B). The accurate modulation of presynaptic release is apparent when measured over a 10-fold range of extracellular calcium (0.3–3 mM; Figure 2C). A similarly accurate modulation of presynaptic release is observed following muscle-specific expression of an inward rectifying potassium channel (Kir2.1), which induces a nonlinear disruption of excitability because Kir2.1 inactivates during excitatory postsynaptic potential (EPSP) depolarization. Nonetheless, a precise increase in presynaptic release offset the disruption of muscle excitation caused by Kir2.1 expression and restored peak EPSP amplitude to control levels (Paradis et al., 2001). Again, compensation is accurate but imperfect since EPSP decay remains more rapid than controls, which will alter summation during a stimulus train (Paradis et al., 2001), an effect similar to that observed at the NMJ of lobster (Pulver Figure 2. Accurate Restoration of Cellular Activity through Homeostatic Signaling et al., 2005). Other examples of accurate compensation are high- (A) Sample traces from cortical pyramidal neurons from wild-type and Kv4.2 lighted in Figures 2D and 2E. One of the greatest challenges in knockout mice (Nerbonne et al., 2008, data from Figure 8 therein). The the field of homeostatic signaling is to define how accurate mod- knockout mice lack the Kv4.2 protein and current. Although acute pharmacological inhibition severely potentiates neuronal excitability, homeostatic ulation achieved. rebalancing of potassium channel expression accurately restores firing There are several features that are commonly employed in properties to wild-type levels. both natural and engineered homeostatic signaling systems (B) Data are shown for recordings made at the Drosophila NMJ. Presynaptic that achieve quantitative accuracy (Stelling et al., 2004). First, release (quantal content) is plotted against spontaneous miniature amplitudes (mEPSP). Each data point is the average data from a single NMJ from control homeostatic systems require a set point that precisely defines NMJ (open black) or NMJ to which philanthotoxin 433 (PhTX) was applied for the output of the system. This is also the state to which the sys- 10 min prior to recording (open red). The line represents ideal homeostatic tem returns after a perturbation. Second, homeostatic systems compensation where any change in mEPSP is offset by an identical percent change in quantal content. The modulation of presynaptic release accurately generally require feedback control to precisely retarget the sys- offsets a broad range of postsynaptic perturbation. tem set point. Homeostatic systems require sensors that detect (C) Data are presented for the Drosophila NMJ plotting excitatory postsynaptic a given perturbation. By analogy, with engineered systems, it is current (EPSC) amplitude versus extracellular calcium concentration. Larvae treated with PhTx (wt + PhTX) accurately retarget control (wt) EPSC ampli- hypothesized that homeostatic signaling systems will require tudes across an order of magnitude change in extracellular calcium. Animals an error signal, representing the difference between the system harboring a loss of function mutation in rim show reduced EPSCs at all calcium set point and steady-state activity reported by the sensors. concentrations. Application of PhTX to rim mutant larvae demonstrates a Finally, the error signal is used to promote a change in homeo- failure of homeostatic compensation at all calcium concentrations (Mu¨ ller et al., 2012). static effectors that drive compensatory changes in the process (D) Intracellular recordings from a stomatogastric neuron in the intact ganglion being studied. These signaling features are often invoked in (control), following removal of the ganglion and placement in organ culture for discussions of neuronal homeostatic signaling. However, at a 10 min (Decentralized) and after 4 days in culture (4 days). After 4 days, the firing properties of the identified neuron are remarkably similar to that molecular level, our understanding remains rudimentary. The observed in the intact animal. Scale bars, 1 s/10 mV. Data modified from challenge is to begin assembling an emerging molecular ‘‘parts Khorkova and Golowasch (2007). list’’ into complete homeostatic signaling system(s) that can (E) Example traces from Xenopus central neurons including control and a explain how quantitatively control of neural activity is achieved. neuron expressing transgenic Kir2.1 (Pratt and Aizenman, 2007). Expression of Kir2.1 induces a change in the underlying current densities, including the sodium current (quantified at right), that help sustain firing properties at control Establishing a Homeostatic Set Point levels. A set point is operationally defined as the physiological state that is held constant by a homeostatic signaling system. It seems that

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This work proposes that individual neurons can express different combinations of ion channels and synaptic strengths in order to arrive at cell-type-specific firing properties. Given the diversity of channels and synapses that participate in neuronal firing, the number of physiologically relevant combination channel densities and synaptic weights that can generate a specific firing pattern is demonstrated to be vast in silico (Prinz et al., 2004; Marder, 2011). Experimental evidence for this type of variation includes the demonstration that anatomically identical cells can have similar firing properties that are driven by diverse combinations of underlying current densities and synaptic weights (Swensen and Bean, 2005; Schulz et al., 2006, 2007; Andra´ sfalvy et al., 2008; Goaillard et al., 2009; Temporal et al., 2012). Mechanistically, it is clear that altered ion channel transcription is involved in the homeostatic rebalancing of ion channel expression (Schulz et al., 2007; Bergquist et al., 2010). Inter- esting data from the lobster stomatogastric system has shown that neuromodulators influence the transcription of ion channels Figure 3. Cell-Autonomous and Synapse-Specific Homeostatic Plasticity in a coordinated fashion (Khorkova and Golowasch, 2007; Tem- (A) Experimental configuration is diagrammed for stimulation and simulta- poral et al., 2012). These data not only highlight the importance neous recording from adjacent CA1 pyramidal neurons in hippocampal of neuromodulation but provide insight into how the homeostatic organotypic culture that are either untransfected (Record:Ctrl, black) or transfected with channel rhodopsin 2 and photostimulated in slice culture for rebalancing of ion channel expression might be constrained. 24 hr, 50 ms light pulses at 3 Hz (Record: Photostim, blue). Below, represen- Another idea is that ion channel translation could also be a tative data are shown for AMPA-mediated currents. Below is a scatter plot of key modulatory step, downstream of the terminal selector. For recording pairs with the mean shown in red. Photostimulation causes a example, a homeostatic change in sodium channel expression decrease in AMPA current due to downscaling and a decrease in synapse number (Goold and Nicoll, 2010). after chronic manipulation of synaptic activity requires the trans- (B) Two neighboring spines with or without overlay of the Syn-YFP terminals lational regulator pumillio, a mechanism that is conserved in both from a Syn-YFP/Kir2.1- overexpressing cell. 2P uncaging of MNI-glutamate flies and mice (Driscoll et al., 2013). Finally, it is also well estab- was elicited at the tip of these spines (yellow crossed lines) and the resulting AMPAR-mediated synaptic current (2P-EPSC) is shown (Vh = À60 mV) (Be´ ı¨que lished that extrinsic factors can influence cell phenotype, one et al., 2011). A postsynaptic potentiation is seen in response to synapse example being neurotransmitter switching (Dulcis et al., 2013). specific presynaptic expression of Kir2.1. Data and images taken from Goold It remains possible that ion channel rebalancing reflects a similar and Nicoll (2010) (A) and Be´ ı¨que et al. (2011) (B). phenotypic switch, albeit more complex. Ultimately, even though we are gaining information about how a cell rebalances ion chan- the establishment of a set point of neuronal activity must be nel expression, a clear model for how the genome defines a cell- related to the specification of cell identity. For example, the firing type-specific set point for neural activity remains elusive. properties of a neuron can be as diagnostic of cell identity as any other anatomical attribute including cell size, dendrite shape, or Sensors the biochemical choice of neurotransmitter. Yet, as emphasized How cells detect a change in neural activity to initiate homeostat- above, ion channel expression, which shapes intrinsic excit- ic plasticity remains unknown. Homeostatic signaling can be ability and neural activity, is not a fixed parameter associated induced cell autonomously (Goold and Nicoll, 2010; Burrone with cell fate. How then is a set point for neuronal activity et al., 2002) and through focal application of TTX to the soma determined? (Ibata et al., 2008). These data are consistent with a somatic It is well established that combinatorial transcription factor sensor of cell-wide activity. As expected, calcium-dependent codes specify cell fate in the nervous system (Jessell, 2000). signaling is essential. For example, both synaptic upscaling Data from C. elegans suggest that cell fate is subsequently main- and downscaling have been shown to require the activity of tained through the action of ‘‘terminal selector’’ transcription fac- CamKK and CamKIV (Goold and Nicoll, 2010; Ibata et al., tors (Hobert, 2011). Terminal selectors are expressed throughout 2008). But the link between altered activity and the induction of life and control the expression of effector genes that define a homeostatic response still remains unclear. Many experiments cellular identity, including ion channels. If a terminal selector is utilize dramatic activity alterations, either blocking activity with deleted, cell fate is not maintained (Hobert, 2011). Perhaps, TTX or inducing seizure-like network activity, which will invoke rather than rigidly controlling ion channel expression, a terminal changes in calcium-dependent signaling and transcription. selector defines which ion channels can be expressed but allows However, there are examples in which moderate and graded channel expression levels to vary according to homeostatic changes in neural activity and muscle depolarization are de- feedback. tected. For example, the magnitude of glutamate receptor inhibi- The idea of a terminal selector remains consistent with tion at the NMJ is precisely offset by an increase in presynaptic groundbreaking theoretical and computational work from the release (Figures 1 and 2) implying a sensor that is able to detect stomatogastric ganglion examining how a set point is retargeted graded changes in muscle excitation. Similarly, moderate through homeostatic feedback (Prinz et al., 2004; Marder, 2011). changes in neuronal firing measured in visual cortex after visual

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deprivation can invoke homeostatic plasticity, leading to the was shown to stimulate expression of Homer1a, which subse- restoration of baseline firing rates (Keck et al., 2013; Hengen quently activates mGluR signaling in an agonist-independent et al., 2013; see also Deeg and Aizenman, 2011). Early efforts manner (Hu et al., 2010). This model is intriguing because the to model homeostatic plasticity in the stomatogastric system control of mGluR subcellular localization has the potential to have emphasized that multiple activity sensors are necessary define the spatial extent of the homeostatic response. In a sepa- to discriminate quantitative differences in neuronal firing (Liu rate set of studies, enhanced network activity induces Plk2, et al., 1998). Yet, biologically, a system of coordinated sensors which phosphorylates the postsynaptic scaffolding protein with the fidelity to follow neural activity remains unknown. SPAR in a CDK5-dependent manner. Subsequent SPAR degra- An interesting possibility is that metabolic sensors may be em- dation weakens the retention of AMPA receptors at the postsyn- ployed in addition to, or in parallel with, changes in intracellular aptic membrane, facilitating synaptic downscaling (Seeburg calcium. In dissociated hippocampal culture, eukaryotic elonga- et al., 2008; Seeburg and Sheng, 2008). Finally, although not tion factor 2 (eEF2) has been implicated as a sensor that can an immediate early gene, retinoic acid has been shown to be detect disruption of glutamatergic transmission (Sutton et al., required for synaptic upscaling, in this case following postsyn- 2004, 2007). Additional work implicates a function for TOR- aptic glutamate receptor inhibition (Wang et al., 2011; Sarti dependent signaling downstream of AMPA receptor blockade et al., 2012). In this model a decrease in dendritic calcium after (Henry et al., 2012). The potential importance of this signaling AMPA receptor blockade induces retinoic acid synthesis and system for homeostasis in vivo is emphasized in experiments subsequent AMPA receptor production (Wang et al., 2011). Ret- demonstrating that TOR signaling is essential for balanced inoic acid acts via the retinoic acid receptor (RAR-a)(Sarti et al., network excitation and inhibition (Bateup et al., 2013). The 2012) and could, potentially, signal cell autonomously (Wang importance of TOR is also emphasized by work at the Drosophila et al., 2011). NMJ in vivo, showing that genetic disruption of TOR and S6 Other advances center on how surface delivery and synaptic Kinase signaling blocks the sustained expression of presynaptic retention of AMPA receptors is controlled so that a homeostatic homeostasis (Penney et al., 2012). In many systems, TOR response can be graded and potentially matched to the magni- signaling is used to detect qualitative changes in the cellular tude of a perturbation. For example, PICK1 (protein interacting environment and, thereby, regulates cellular homeostasis and with C-kinase) scaffolds an intracellular AMPA receptor pool. growth (Laplante and Sabatini, 2012). As such, it is a candidate There is evidence that PICK1 levels are decreased in a graded for detecting quantitative changes in neural function and stimu- fashion in response to chronic activity inhibition, releasing lating downstream homeostatic plasticity. AMPA receptors for translocation to the plasma membrane (Anggono et al., 2011). Other work focuses on how AMPA recep- Homeostatic Effectors: Synaptic Scaling tors are retained at the postsynaptic density by PSD95, PSD93, Synaptic scaling is expressed as a change in neurotransmitter and SAP102. It has been shown that PSD95 and SAP102 levels receptor abundance. Although a great deal has been discovered are modulated bidirectionally by neural activity (Sun and Turri- about the transcription, assembly, and trafficking of glutamate giano, 2011). In this study, PSD95 is shown to be necessary receptors, the mechanisms that control receptor trafficking in a but not sufficient for synaptic scaling, acting through the regu- homeostatic fashion remain largely unknown. Many key issues lated organization of the postsynaptic scaffold (Sun and Turri- remain to be molecularly defined, including how synaptic scaling giano, 2011). Clearly, there will be additional complexity as an is achieved in a cell-wide fashion with proportional effects at increasing number of molecules are shown to be necessary for every active zone. Similarly, there is very little information to synaptic scaling including MHC1 (Goddard et al., 2007), BDNF explain how the synaptic scaling mechanism becomes limited (Rutherford et al., 1998; Jakawich et al., 2010; Correˆ a et al., as neuronal firing properties are restored toward baseline, set 2012), and Beta3-integrins (McGeachie et al., 2011). point levels, and how the system is eventually shut off (but see Tatavarty et al., 2013). In attempting to define how the homeo- Homeostatic Effectors: Presynaptic Homeostasis static control of glutamate receptor trafficking is achieved, it is The power of model system forward genetics in Drosophila has useful to make comparisons to nonneuronal systems in which opened the door to a mechanistic understanding of presynaptic homeostatic control of surface transporters and ion channels homeostasis. An electrophysiology-based forward genetic has been defined without the added complexity of cell diversity. screen is ongoing, based on intracellular recordings of neuro- These systems include trafficking of ENaC channels during the muscular transmission, to identify mutations that prevent the ho- systemic control of salt balance and trafficking of the Glut4 meostatic enhancement of presynaptic neurotransmitter release glucose transporter during glucose homeostasis (Lifton et al., after pharmacological inhibition of postsynaptic glutamate 2001; Martin et al., 2006; Leto and Saltiel, 2012). Several ad- receptors (Dickman and Davis, 2009; Mu¨ ller et al., 2011; Younger vances are highlighted here that provide insight into emerging et al., 2013). To date, more than 1,000 mutations and RNAi have homeostatic control of glutamate receptor trafficking. been tested (Dickman and Davis, 2009; Mu¨ ller et al., 2011; The induction of synaptic scaling has been an area of consid- Younger et al., 2013). Based largely on the results of this forward erable progress. An emerging theme is the activity-dependent genetic approach, a model has emerged to explain how synaptic induction of immediate early gene signaling including Homer1a, vesicle release is precisely potentiated at the NMJ. Arc (Arg3.1), Narp, and Polo-like kinase 2 (Plk2) (Seeburg et al., Two presynaptic processes converge to potentiate vesicle 2008; Hu et al., 2010; Chang et al., 2010; Be´ ı¨que et al., 2011; fusion during presynaptic homeostasis: (1) potentiation of pre- Shepherd et al., 2006). In one study, enhanced network activity synaptic calcium influx and (2) potentiation of the readily

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blocks presynaptic homeostasis (Figure 2C), was particularly informative. When the homeostatic modulation of presynaptic calcium influx and RRP size were tested in RIM mutants, only the modulation of the RRP was blocked and synaptic homeostasis was prevented (Mu¨ ller et al., 2012). The means by which RIM mediates this activity has yet to be determined. The RIM- interacting molecules Rab3 and Rab3-GAP also participate in presynaptic homeostasis (Mu¨ ller et al., 2011). In mammalian systems, these molecules establish a biochemical bridge between the calcium channel and the synaptic vesicle (Han et al., 2011; Kaeser et al., 2011). This may represent a central, regulated scaffold that coordinates the homeostatic modulation of the RRP with calcium entry. Additional genes have been found to be essential for presynaptic homeostasis including postsynaptic scaffolding (Pilgram et al., 2011), postsynaptic TOR/S6K (Pen- ney et al., 2012), and micro-RNA signaling (Tsurudome et al., 2010), all nicely summarized in a recent review of homeostatic plasticity at the Drosophila NMJ (Frank, 2013). Parallels have emerged at mammalian central synapses, Figure 4. Presynaptic Homeostasis Is Achieved by Parallel Changes consistent with the homeostatic modulation of both vesicle pools in the Size of the Readily Releasable Vesicle Pool and Presynaptic and presynaptic calcium influx. Chronic activity blockade has Calcium Influx (A and B) Variance-mean analysis supports a RIM-dependent modulation of been shown to cause a correlated increase in both presynaptic the RRP during synaptic homeostasis. (A) Example EPSC traces for a WT NMJ release and calcium influx, imaged simultaneously through at the indicated extracellular calcium concentration (millimolar). (B) Example coexpression of transgenic reporters for vesicle fusion and EPSC amplitude variance-mean plots of two WT synapses in the absence calcium (Zhao et al., 2011). Mechanistically, presynaptic CDK5 (gray) and presence (black) of PhTX with parabola fits (solid lines) that were extrapolated to the x intercept (dashed lines; see Mu¨ ller et al., 2012). has been implicated. Loss or inhibition of CDK5 potentiates pre- (C) Representative traces for measurement of the spatially averaged calcium synaptic release by promoting calcium influx and enhanced signal within synaptic boutons at the NMJ in a wild-type (control) and GluRIIA access to a recycling pool of synaptic vesicles. Chronic activity mutant. The homeostatic enhancement of presynaptic release is correlated with a statistically significant increase in the peak amplitude of the spatially suppression phenocopies these effects and causes a decrease averaged calcium signal (see Mu¨ ller and Davis, 2012). in synaptic CDK5 implying a causal link (Kim and Ryan, 2010). The activity of CDK5 has been shown to be balanced by calci- releasable pool (RRP) of synaptic vesicles (Figure 4). First, a neurin A and, together, these molecules act via the CaV2.2 combination of calcium imaging and genetic data demonstrate calcium channel (Kim and Ryan, 2013). Remarkably, the CDK5/ that an increase in presynaptic calcium influx through the Calcineurin-dependent modulation of presynaptic release has CaV2.1 calcium channel is necessary to achieve a homeostatic sufficient signaling capacity to cause the silencing and unsilenc- increase in vesicle release (Mu¨ ller et al., 2011, 2012). A surprising ing of individual active zones in hippocampal cultures (Kim and mechanism is employed to modulate presynaptic calcium influx. Ryan, 2013). The involvement of a presynaptic DEG/ENaC sodium leak channel was uncovered in the aforementioned genetic screen. In the Enabling a Homeostatic Response through Permissive emerging model, presynaptic DEG/ENaC channel insertion at or Signaling near the nerve terminal causes low-voltage modulation of the Studies at the Drosophila NMJ and mammalian central synapses presynaptic resting potential due to sodium leak and subsequent demonstrate that secreted factors create an environment that is potentiation of presynaptic calcium influx (Figure 5). This model necessary for the expression and/or maintenance of homeostat- is attractive because it provides an analog mechanism that could ic plasticity including both presynaptic homeostasis and post- fine-tune presynaptic calcium influx according to the demands synaptic scaling. Since these factors do not dictate the timing of the homeostatic signaling system. Low-voltage modulation or magnitude of the homeostatic response, they are consid- of neurotransmitter release has been observed in systems ered essential, permissive cues. At the Drosophila NMJ, bone ranging from the crayfish NMJ to the rodent hippocampus (Woj- morphogenetic protein (BMP) signaling from muscle to moto- towicz and Atwood, 1983; Awatramani et al., 2005; Christie et al., neuron drives NMJ growth during larval development (McCabe 2011), although links to homeostatic plasticity have not been et al., 2003). Subsequently, it was demonstrated that genetic made in these systems. Interestingly, ENaC channels can be deletion of the BMP ligand, a presynaptic BMP receptor, or considered as homeostatic effector proteins during the systemic downstream transcription all blocks synaptic homeostasis control of salt balance (Lifton et al., 2001). (Goold and Davis, 2007). Importantly, BMP signaling does not Remarkably, the potentiation of presynaptic calcium influx function at the NMJ to instruct a change in neurotransmitter alone is not sufficient to drive a homeostatic change in synaptic release. Instead, BMP-dependent transcription permits the in- vesicle fusion. A parallel increase in the RRP of synaptic vesicles duction of synaptic homeostasis, which is expressed locally at is required (Weyhersmu¨ ller et al., 2011; Mu¨ ller et al., 2012). An the NMJ. The nature of the permissive signal downstream of analysis of mutations in RIM (Rab3 Interacting Molecule), which BMP-dependent transcription remains unknown (Goold and

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Figure 5. Emerging Model for the Expression of Presynaptic Homeostasis Schematic of an active zone at the Drosophila NMJ shows presynaptic CaV2.1 calcium channels (blue), the action potential triggered calcium microdomain (red), postsynaptic glutamate receptors (GluRIIA, dark gray), and presynaptic ENaC channel (pink). Two genes, pickpocket11 and pickpocket16, were discovered to be necessary, presynaptically, for the rapid induction and sustained expression of presynaptic homeostasis (Younger et al., 2013). These genes encode sub- units of an Epithelial/Degenerin (ENaC) sodium leak channel. These genes are cotranscribed and transcriptionally upregulated after persistent disruption of postsynaptic glutamate receptor function. These and other data support a model in which ENaC channel insertion drives a modest depolarization of the presynaptic resting potential (DV), which enhances presynaptic calcium and neurotransmitter release. A parallel change in the readily releasable pool of vesicles is also necessary for synaptic homeostasis, which relies on the presynaptic adaptor proteins RIM (Mu¨ ller et al., 2012) and RIM binding protein (RBP) (green). When both processes are enabled, a homeostatic enhancement of release is observed. A number of additional synaptic proteins have been shown to be required for presynaptic homeostasis (dark blue text). Among them, there is evidence for the involvement of micro-RNA-based signaling (Mir10, gray; Tsurudome et al., 2010) and permissive BMP-mediated signaling released from muscle (gray) and acting at the motoneuron soma (gray; Goold and Davis, 2007). Postsynaptically, there is evidence for the required function of Tor and S6K as well as Dystrobrevin-dependent scaffolding (Penney et al., 2012; Pilgram et al., 2011). Figure modiﬁed from Younger et al. (2013). Additional molecular mechanisms involved in presynaptic homeostasis have been recently reviewed (Frank, 2013).

Davis, 2007). A related function has been proposed for TNF-a at control to ensure a robust, reproducible outcome (Baumgardt mammalian central synapses. TNF-a is required for synaptic et al., 2007). From this perspective, homeostatic plasticity might scaling, is released from glia in response to prolonged activity serve to correct developmental inaccuracies but would not be blockade, and is sufficient to drive synaptic scaling (Beattie invoked as part of normal developmental signaling. Data from et al., 2002; Stellwagen et al., 2005; Stellwagen and Malenka, the Drosophila NMJ support this idea. 2006). But it was recently demonstrated that the rapid induction The NMJ of Drosophila larvae grow 100-fold in volume of synaptic scaling after 4–6 hr of activity blockade is normal in during a 5-day period of postembryonic development. In the absence of TNF-a. Synaptic scaling is only blocked if TNF- Drosophila, as in most systems, when a muscle fiber grows a is removed >12 hr prior to activity blockade. It is argued, based the input resistance drops precipitously, requiring enhanced on these data, that TNF-a is a permissive signal that maintains presynaptic release to achieve constant muscle depolarization synapses in a state amenable to homeostatic modulation (Stein- (Davis and Goodman, 1998a). However, presynaptic homeosta- metz and Turrigiano, 2010). While the relevance of permissive sis does not appear to be involved. Forward genetic screening homeostatic signaling remains to be determined, permissive has identified several mutations that block presynaptic homeo- signaling could be used to control whether or not homeostatic stasis without altering anatomical or functional neuromuscular plasticity is expressed at different times during development development (Dickman and Davis, 2009; Mu¨ ller et al., 2011; (Maffei and Fontanini, 2009; Echegoyen et al., 2007) and its in- Younger et al., 2013). This observation was extended by recent duction in the context of stress or disease (Goold and Davis, work using the ENaC channel blocker benzamil to acutely disrupt 2007; Steinmetz and Turrigiano, 2010). presynaptic homeostasis. Benzamil was applied to the NMJ of animals lacking the muscle-specific GluRIIA glutamate receptor Interface of Development and Homeostatic Plasticity subunit, a perturbation that is persistent throughout develop- The nervous system is remarkably plastic during development. ment and induces presynaptic homeostasis. Benzamil erased Individual neurons and muscle change dramatically in size and the expression of presynaptic homeostasis, leaving behind a complexity. Synaptic connectivity is refined through mecha- synapse with unpotentiated wild-type release and wild-type nisms of synaptic competition. New cells are integrated into fully anatomy (Younger et al., 2013). Together, these data demon- functioning neural circuitry. Do these changes represent pertur- strate that presynaptic homeostasis is uncoupled from the bations that are stabilized by homeostatic signaling? One mechanisms that achieve anatomical and physiological NMJ approach has been to define the cellular parameters that are growth. One possibility is that presynaptic homeostasis is only held constant during periods of developmental growth, but this induced developmentally when a cellular set point differs from has not defined whether constancy is achieved through homeo- ongoing activity. If the set point is developmentally programmed static control (Bucher et al., 2005). Answering this question is to change along with the maturation of cell fate, then a develop- likely to be important for understanding how homeostatic plas- mental change in cellular function could occur without the induc- ticity might participate in diseases including autism spectrum tion of homeostatic plasticity. disorders (ASDs) and schizophrenia that can be traced back to In the mammalian CNS, homeostatic and developmental plas- alterations in early brain development (Ramocki and Zoghbi, ticity coexist. This is nicely documented in a binocular region of 2008; Bourgeron, 2009). The construction of an embryo from a visual cortex after monocular deprivation (Mrsic-Flogel et al., single cell is a tightly choreographed process that includes 2007). When cells receive input predominantly from an open inductive signaling with both negative and positive feedback eye, deprived eye input is diminished, consistent with classical

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