Diverse facets of cortical interneuron migration regulation – Implications of neuronal activity and epigenetics

Accepted Manuscript Review Diverse facets of cortical interneuron migration regulation - implications of neuronal activity and epigenetics Geraldine Zimmer-Bensch PII: DOI: Reference:

S0006-8993(18)30459-1 https://doi.org/10.1016/j.brainres.2018.09.001 BRES 45933

To appear in:

Brain Research

Received Date: Revised Date: Accepted Date:

10 June 2018 2 September 2018 3 September 2018

Please cite this article as: G. Zimmer-Bensch, Diverse facets of cortical interneuron migration regulation implications of neuronal activity and epigenetics, Brain Research (2018), doi: https://doi.org/10.1016/j.brainres. 2018.09.001

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Diverse facets of cortical interneuron migration regulation - implications of neuronal activity and epigenetics

Author:

Geraldine Zimmer-Bensch*

Affiliation:

Department of Functional Epigenetics in the Animal Model Institute for Biology II RWTH Aachen University Worringerweg 3 52074 Aachen Germany

Phone:

0241 8020844

Email:

[email protected]

*corresponding author Abstract The proper function of the cerebral cortex relies on the delicate balance of excitation and inhibition determined by the accurate number and subtype composition of the diverse group of inhibitory gamma-aminobutyric (GABA)-expressing interneurons. Developmental defects can lead to impaired cortical inhibition and seem implicated in neuropsychiatric disorders like schizophrenia. The multifaceted development of cortical interneurons, of which the long-range migration from the basal telencephalon to cortical targets represents a critical step, is orchestrated by various intrinsic and extrinsic factors. Besides motogenic factors, neuronal activity determined by neurotransmitter and calcium signaling turned out as a crucial driver of cortical interneuron motility and migration, whereas the directionality is orchestrated by specific guidance receptors. Thereby, the responses towards different guidance and neurotransmitters cues appear highly stage and cell type- specific, relying on a complex transcriptional network that instruct the expression of particular receptor combinations. The contribution of epigenetic mechanisms to gene expression control that direct cortical interneuron migration and maturation are now beginning to be approached. This is key to decipher interneuron subtype-specific

developmental

programs

and

helps

to

understand

how 1

environmental signals can shape subtype-specific maturation. This review provides an overview about the achievements that were made in uncovering the regulatory networks orchestrating the migration of distinct cortical interneuron subtypes with focus on the role neuronal activity and epigenetic transcriptional control.

Keywords: GABA, glutamate, DNMT1, DNA methylation, histone modifications

Abbreviations: MGE medial ganglionic eminence POA pre-optic area CGE caudal ganglionic eminence

Acknowledgements: I thank Jessica Demontfort for critical reading of the manuscript. I apologize to all colleagues whose publications I was not able to cite due to reasons of space limitations.

Funding Resources This work was supported by the DFG (ZI1224/4-1) and the IZKF Jena.

Introduction Neuronal circuitries in the mammalian cerebral cortex, the seat of higher cognitive functions, are composed of excitatory glutamatergic principal neurons and inhibitory gamma-aminobutyric acid (GABA)-expressing interneurons. The active modulation of excitatory responses by inhibitory interneurons is critical for cortical information processing, cortical plasticity, as well as learning and memory formation (Hensch, 2005; Letzkus et al., 2015). Due to their immense morphological and physiological heterogeneity, inhibitory interneuron subtypes have the capacity to selectively target different sub-cellular compartments of projection neurons (De Marco Garcia et al., 2011) allowing for a dynamic inhibition-dependent regulation of input and output processing (Gidon and Segev, 2012; Pouille et al., 2013). Defective development or 2

function of particular GABAergic interneuron subsets are implicated in diverse neurologic and psychiatric diseases like schizophrenia, epilepsy and autism (Marin, 2012). For this, understanding the principles orchestrating the assembly of cortical circuits and the development of their diverse neuronal composites is prerequisite to reveal critical events that lead to the manifestation of neurological or neuropsychiatric disorders. In contrast to excitatory cortical neurons that arise from the cortical proliferative zones, the different subsets of inhibitory GABAergic interneurons are generated in spatially distinct domains of the basal telencephalon. These include the medial and caudal ganglionic eminences, abbreviated with MGE and CGE, respectively (Anderson et al., 2001; Corbin and Butt, 2011; Marin and Rubenstein, 2001; Miyoshi et al., 2010; Wichterle et al., 2001), as well as the pre-optic area (POA) (Anderson et al., 2001; Gelman et al., 2011; Gelman et al., 2009). Each interneuron generating domain contributes to a variety of cortical interneuron subtypes in addition to neurons fated for diverse destinations. Besides cortical interneurons, which include parvalbumin (PV)-positive basket and chandelier cells, as well as Martinotti and multipolar somatostatin (SST)-expressing interneurons (Butt et al., 2005; Butt et al., 2008; Xu et al., 2003), the MGE gives rise to neurons fated for the striatum, a region cortical interneurons avoid on their way to the cortex, as well as to neurons of the globus pallidus (Flandin et al., 2010; Marin et al., 2000; Nobrega-Pereira et al., 2010). Similarly, the POA contributes to a diverse subset of cortical interneurons, including neuropeptide Y (NPY)-, reelin-, PV-, SST-, CTIP2positive interneurons and neurogliaform cells, as well as to residual POA cells and neurons populating other telencephalic regions (Gelman et al., 2011; Gelman et al., 2009; Niquille et al., 2018; Rubin and Kessaris, 2013; Symmank et al., 2018b). Likewise, the CGE generates a large variety of cortical interneurons including reelinpositive cells, vasointestinal peptide (VIP)/calretinin-positive bipolar interneurons and VIP/cholecystokinin-positive basket cells (Miyoshi et al., 2010; Murthy et al., 2014; Rubin and Kessaris, 2013). Upon becoming post-mitotic, the different interneuron subsets migrate along particular routes through the basal telencephalon up to the cortex (Corbin and Butt, 2011; Marin and Rubenstein, 2001). This long-range tangential migration to cortical target regions represents a critical step. Apart from initiation of migration by adapting a migratory morphology and the maintenance of their motility throughout the 3

migratory period, the directionality has to be strictly controlled to achieve successful migration to the cortex, to precisely distribute over cortical areas and layers, and to finally integrate appropriately into cortical circuits (Hernandez-Miranda et al., 2010; Metin et al., 2006; Miyoshi et al., 2010; Tanaka and Nakajima, 2012). Regulation of cortical interneuron migration Distinctive migratory trajectories have been proposed for interneurons deriving from different subpallial domains but also for interneurons originating in the same proliferative region. While a prominent fraction of MGE-derived interneurons follows a deep route through the SVZ (Ang et al., 2003; Rudolph et al., 2010; Steinecke et al., 2014; Sussel et al., 1999; Wichterle et al., 2001; Wichterle et al., 2003; Zimmer et al., 2011), also superficially migrating MGE-interneurons towards and within the cortex were observed (Li et al., 2008; Lim et al., 2018; Lopez-Bendito et al., 2008). Lim et al. (2018) have reported that predominantly Som-expressing interneurons migrate superficially, while the majority of the NKX2-1 population follows the deep trajectory. Similar observations were made for POA-derived interneurons. Although a large proportion migrates superficially, a cohort of cells prefers the deep trajectory within the basal telencephalon and the developing cortex (Gelman et al., 2009; Niquille et al., 2018; Pensold et al., 2016; Symmank et al., 2018b). Interneurons generated in the CGE likewise follow different migratory routes. Moreover, three migratory streams have been described so far for CGE-derived interneurons. Besides the caudal migratory stream (Miyoshi et al., 2015; Yozu et al., 2005), two caudal-rostro trajectories were described for CGE-derived interneurons in mice, a lateral (LMS) and medial migratory stream (MMS) (Touzot et al., 2016). As each interneuron generating domain gives rise to diverse cortical interneuron subtypes as well as to neurons fated for other telencephalic regions, it is conceivable that migratory preferences rely on subtype identity, equipped with a particular repertoire of guidance receptor driven by subtype-specific transcriptional programs to explicitly respond to local guidance cues. In support of this, post-mitotic interneurons from the same domain express varying sets of guidance receptors, as revealed by single cells analysis (Pensold et al., 2016). Guidance receptors bind to membrane-bound or secreted guidance cues involving several protein families as well as proteoglycans that elicit repulsive or attractive 4

responses.

Neuregulins act as short and long-range attractants for ERBB4-

expressing MGE-interneurons (Flames et al., 2004). Moreover, CXCL12-induced chemotaxis is required for proper migration of MGE-derived interneurons to and within the cortex, integrated through CXCR4 and CXCR7 receptors (Lopez-Bendito et al., 2008; Sanchez-Alcaniz et al., 2011; Wang et al., 2011; Yozu et al., 2005). Besides attractive cues, a battery of repellent factors expressed in regions flanking the migratory corridor helps to channel and direct cortical interneuron migration. An important family of repulsive guidance cues is the membrane-bound ephrins and their receptors, the Eph-receptor tyrosine kinases (EPH-receptors). In addition to ephrininduced activation of EPH-receptors, EPH-receptors can initiate signaling events in ligand-expressing cells, which is called forward and reverse signaling, respectively (Drescher, 2002). Many MGE-derived interneurons express EPHA4 (Pensold et al., 2016; Zimmer et al., 2008; Zimmer et al., 2011), through which they are repelled from the ventricular zone and the developing striatum positive for ephrin-A5 and ephrin-A3 ligands, respectively (Hernandez-Miranda et al., 2011; Rudolph et al., 2010; Zimmer et al., 2008). Furthermore, ephrin-B3 is expressed in a subset of POA-derived interneurons (Pensold et al., 2016) which provokes repulsive responses in MGEderived cortical interneurons interacting with EPHA4, while EPHA4 in turn acts as repellent cue for ephrin-B3-positive POA cells via reverse signaling (Zimmer et al., 2011). Repulsive ephrin-B3-mediated reverse signaling is also important for POA-derived cortical interneurons avoiding the developing striatum on their way to the cortex, induced by EPHB1 (Pensold et al., 2016; Rudolph et al., 2014). Besides cortical interneurons, the POA generates islet-1-positive striatal neurons (Elshatory and Gan, 2008), which also express ephrin-B3 (Pensold et al., 2016). In contrast to cortical interneurons, where EPHB1-mediated activation of ephrin-B3 stimulates repulsion, it acts as a stop-signal for striatal-fated neurons. Distinct intrinsic signaling cascades mediate differential responses in striatal versus cortical interneurons (Rudolph et al., 2014). In addition to EPHB1, the developing striatum expresses semaphorin-3A and semaphorin-3F, which elicit repulsive responses in neuropilin-1 and neuropilin-2positive cortical interneurons (Marin et al., 2001). As neuropilin-2 receptors are expressed in MGE and POA-derived interneurons (Garcia et al., 2016; Zimmer et al.,

5

2011), semaphoring/neuropilin signaling seems required for cortical interneurons independent of their site of origin for being repelled from the striatum. Furthermore, chondroitinsulfate-proteoglycans are evident in the embryonic striatal anlage, shown to bind secreted SEMA3A, which is suggested to enhance the repulsive potential of the developing striatum for neuropilin-1-positive interneurons (Zimmer et al., 2010). Moreover, ROBO1 interactions with neuropilin-1 modulate the semaphorin-neuropilin/plexin signaling, thereby guiding cortical interneurons around the striatum (Hernandez-Miranda et al., 2011).

Apart from directionality, interneuron motility is crucial for proper long-range migration up to the cortex, which is supported by motogenic factors. Besides the hepatocyte growth factor described as a motogen for migrating cortical interneurons (Powell et al., 2001), EPHA4 can act as a motogenic factor for MGE-derived interneurons mediated by ephrin-A2 reverse signaling (Steinecke et al., 2014). In addition, GABA and glutamate were described to promote interneuron motility. Thereby, the stimulatory action of GABA seems to rely on its depolarizing function during development (Luhmann et al., 2015), determined by a high to low ratio of NKCC2 and KCC2 expression (Ben-Ari, 2002). The up-regulation of the potassium-chloride cotransporter KCC2 in turn appears essential for the termination of cortical interneuron migration (Bortone and Polleux, 2009; Inamura et al., 2012), inducing the developmental switch from depolarizing to hyperpolarizing action of GABA upon GABAA receptor activation (Ben-Ari, 2002). These studies imply a participation of neuronal activity in the regulation of cortical interneuron migration, which will be discussed in more detail in the next section. Activity-dependent regulation of interneuron migration Several studies already provided evidence for an important role of activity in neuronal migration, including neurotransmitter signaling and calcium transients (Babij and De Marco Garcia, 2016; Uhlen et al., 2015). Besides its well-documented function during the migration of glutamatergic neurons (Bando et al., 2016; Behar et al., 1999; Behar et al., 2000; Bony et al., 2013; Heck et al., 2007; Kihara et al., 2002; Liu et al., 2008; Liu et al., 2010; Luhmann et al., 2015), evidence exists for the relevance of activity regulation in modulating GABAergic interneuron migration. Thereby, the activitydependent regulation of migration emerges as a multifaceted process, appearing 6

specific for distinct cortical interneuron subtypes and seems to rely on different mechanisms during tangential versus radial interneuron migration (De Marco Garcia et al., 2011; De Marco Garcia et al., 2015). While inhibiting neuronal excitability of CGE-derived interneurons in vivo by forced expression of the inward rectifying potassium channel Kir2.1 at E15.5 caused no changes in tangential migration, a shift in radial allocation towards deeper cortical layers was observed at later stages (De Marco Garcia et al., 2011). Alongside with this stage-specific effect, the activity dependent regulation of radial migration seems to affect only particular interneuron subsets. While calretinin and reelin-positive interneurons displayed altered layer distribution, VIP-positive cells were not affected (De Marco Garcia et al., 2011). Such cell type specificity of glutamate-dependent activity regulation was further observed for the morphological maturation of cortical interneurons, with reelin but not VIPpositive cells showing a vulnerability towards attenuation of cortical glutamatergic activity, which is mediated by NMDAR function (De Marco Garcia et al., 2015).

Functional implications of glutamate in cortical interneuron migration In addition to NMDARs, AMPARs as another type of ionotropic glutamate receptors are expressed in migrating GABAergic interneurons (Bortone and Polleux, 2009; Yozu et al., 2008). Inhibition of both, NMDA and AMPA receptors, impedes the migration of cortical inhibitory interneurons (Bortone and Polleux, 2009), pointing to a stimulatory role of glutamate for interneuron motility. However, discrimination between AMPAR and NMDAR signaling in promoting interneuron migration was not performed and necessitates further investigations, especially as AMPAR activation seems to have the opposite effect on the migration of cortical interneurons once they have reached the cortex. While no obvious AMPA-induced effects were observed for interneurons migrating through the ganglionic eminences (Yozu et al., 2008), AMPAR activation in interneurons tangentially migrating within the cortex induces neurite retraction (Poluch et al., 2001) and a stop in migration or a change in direction (Yozu et al., 2008). Together with the study of Bortone and Polleux (2009), these observations reflect divergent roles of glutamate during the developmental time course, which could be caused by differential expression of glutamate receptor types expressed during early migration versus later migration within the cortex. In support of this, the calcium-permeable GluR1 subunit of AMPAR was only detected in interneurons migrating within the cortex but not through the subpallium (Metin et al., 7

2000; Yozu et al., 2008). The pro-migratory function glutamate has on glutamatergic cortical neurons (Behar et al., 1999; Behar et al., 2000; Hirai et al., 1999) occurs through Ca2+-permeable NMDA receptors (Behar et al., 1999; Hirai et al., 1999), and overexpression of the NR2B NMDAR subunit promotes the migratory activity of cerebellar granular cells (Tarnok et al., 2008). Hence, the initial migration promoting function of glutamate on cortical interneurons could be mediated by NMDAR signaling, while the up-regulation of calcium-permeable AMPARs in interneurons that have reached the cortex could induce the switch of glutamate function from a promigratory to a stop signal. Yet, in hippocampal interneurons, glutamate-dependent AMPAR signaling was shown to facilitate their migration (Manent et al., 2006), and NMDAR function seems at least for a subset of reelin-positive and somatostatinnegative cortical interneurons crucial for their morphological maturation at later stages within the cortex, as revealed by conditional deletion of the NR1 and NR2B NMDA receptor subunits (De Marco Garcia et al., 2015). However, as mice lacking the NR1 NMDAR subunit did not display gross defects in cortical architecture that would point to strong migratory defects in general (Iwasato et al., 2000), the role of NMDAR signaling in regulating the migration of both, cortical GABAergic interneurons and excitatory neurons, in vivo is still vague and certainly needs further investigations to make final conclusions. Thereby, it would be crucial to dissect the cell type and stage-specific functions of glutamate on cortical interneuron migration, with focus on the different glutamate receptors and associated downstream signaling events.

The role of GABA in cortical interneuron migration Besides glutamate, several in vitro and in vivo studies propose a role of GABA in controlling cortical interneuron migration. Migratory interneurons express GABARs and GABA-induced signaling is crucial for proper migration (Cuzon et al., 2006; Lopez-Bendito et al., 2003). As revealed by pharmacological manipulations, GABA-A receptor antagonists decrease the proportion of interneurons tangentially migrating into the cortex, whereas GABA-A receptor agonists induce the contrary effect (Cuzon Carlson and Yeh, 2011; Cuzon et al., 2006; Kilb et al., 2013). While type A GABAR (GABAAR) signaling seems to be required for interneurons to traverse the corticalstriatal notch promoting the cortical entry of interneurons (Cuzon et al., 2006), type B GABAR (GABABR) signaling modulates the navigation of interneurons within the 8

developing cortex (Lopez-Bendito et al., 2003). Consistently, in vivo studies showed that diazepam, a GABA receptor agonist, increases motility, whereas blocking GABA-A receptors and sodium-potassium-chloride co-transporters (NKCC1), as well as chelating intracellular calcium diminishes the motility of tangentially migrating interneurons (Inada et al., 2011). During embryonic and early postnatal development, GABA is depolarizing, which is determined by a high expression of NKCC1 and low KCC2 levels (Ben-Ari, 2002; Kirmse et al., 2015). Increasing KCC2 expression is associated with the switch from the depolarizing GABA action in immature interneurons to its hyperpolarizing function (Ben-Ari, 2002). As described for glutamate receptor signaling, GABA can act as a pro-migratory as well as a stop signal, which seems associated to its NKCC1 and KCC2-dependent depolarizing and hyperpolarizing function, respectively. While GABA-induced depolarization seems to promote interneuron motility, the hyperpolarizing action turns GABA into a stop signal (Bortone and Polleux, 2009). Contradicting these studies, GAD67-GFP knockin and GAD67 knockout mice lack gross brain cytoarchitectonic defects that are indicative of migratory defects (Asada et al., 1997; Furukawa et al., 2014), although GABA levels were found remarkably reduced in P0.5 GAD67 knockout mice (Asada et al., 1997). A possible explanation could be that taurine (2-aminoethanesulfonic acid), the most abundant amino acid in the CNS (Benitez-Diaz et al., 2003; Huxtable, 1989), represents an important endogenous agonist of GABARs, which was already reported to influence at least the radial migration of cortical neurons (Furukawa et al., 2014). Taurine further inhibits KCC2 activity by triggering the with-no-lysine protein kinase (WNK) signaling pathway (Inoue et al., 2012), through which it might additionally contribute to maintain the depolarizing GABAergic responses underlying the pro-migratory function in immature neurons. As the concentration of taurine is found substantially higher than for GABA (Qian et al., 2014), and as pharmacological blockade of taurine synthesis elicits stronger effects on migration than the one observed in GAD67deficient mice (Furukawa et al., 2014), taurine is considered as an important endogenous agonist acting on migration through GABAR activation and could compensate for the decline of GABA in GAD67 knockout mice in regard to migratory regulation.

Potential sources of GABA and glutamate acting on migration 9

The source of extracellular glutamate as well as GABA acting on neuronal migration is not completely known. Glutamate as well as GABA can be released in a SNAREindependent manner shown by studies using hippocampal organotypic slice cultures, in which vesicular transmitter release was abolished. Thereby, both transmitters modulate neuronal migration through paracrine actions (Manent et al., 2005). Transporters represent another mechanism of extracellular transmitter control. Extracellular glutamate levels are known to be determined by glutamate uptake via transporters expressed in astrocytes (Thomas et al., 2011) and inhibition of glutamate uptake enhances migration (Komuro and Rakic, 1993). For tangentially migrating interneurons in the rat cortical intermediate zone, a nonvesicular release of GABA via reverse action of GAT-1, a transporter involved GABA uptake from the interstitial space, has been shown. This GABA release was induced by glutamate-mediated activation of AMPA receptors and sodium influx (Poluch and Konig, 2002). In the cortical marginal zone, representing the superficial migratory path of inhibitory interneurons, GABA release through GAT2/3 transporters has been reported, whereby their operating mode is influenced by excitatory amino acid transporters (EAATs) via intracellular sodium signaling and/or cell depolarization (Unichenko et al., 2013). Alternatively, GABA could be released via anion channels such as the bestrophin-1 channel (Lee et al., 2010). Whereas direct evidence is still lacking for GABA release via volume-sensitive anion channels, taurine release through volume-sensitive anion channels was identified (Furukawa et al., 2014).

Dopamine and Serotonin signaling during GABAergic interneuron migration In vitro as well as in vivo studies propose an opposing role of dopamine-induced signaling in interneuron migration, dependent on the receptor. While D1 receptor activation promotes the migration of MGE and CGE-derived GABAergic interneurons in vitro, D2 receptor activation had the opposite effect (Crandall et al., 2007). These results were confirmed by D1 and D2 knockout mice (Crandall et al., 2007). In vitro data using time lapse imaging of slice cultures further suggest that 5-HT decreases interneuron migration through the activation of 5-HT6 serotonin receptors (Riccio et al., 2009). Although a mouse model displaying high levels of extracellular 5-HT (Slc6a4 knockout mice) did not display a phenotype that would support a general negative effect of 5-HT on migration, the authors found a changed distribution of GAD65-GFP interneurons in the cortex at birth (Riccio et al., 2009). 10

Likewise, Frazer et al. (2015) reported a mispositioning of CGE-derived cortical interneurons upon SERT deficiency, which also causes high levels of extracellular serotonin, whereby VIP and NPY-positive CGE-derived interneurons were affected (Frazer et al., 2015). Positioning defects of particular CGE but not MGE-derived interneuron subsets were further detected upon the loss of 5-HT3a serotonin receptor function, which is selectively expressed in CGE-derived cells and which becomes upregulated upon cortical entry (Murthy et al., 2014). Beyond that, Frazer et al. (2015) reported that early-life SERT deficiency increases the migratory speed of CGEderived interneurons. This is opposed to what was found by Riccio et al. (2009) for GAD65-GFP cells, and might be explained with subset-specific receptor expression and associated down-stream signaling. Hence, like for GABA and glutamate, dopamine and serotonin-induced effects on migration appear cell type and stagespecific, requiring more detailed analysis.

Calcium as common mediator in downstream signaling The downstream pathways of glutamate, serotonin, dopamine and GABA-dependent migration regulation are still not well understood, but seem to involve increased intracellular calcium levels that could transduce activity into discrete intracellular signals eliciting differential responses

(Behar et al., 1999; Bortone and Polleux,

2009; Inada et al., 2011; Komuro and Kumada, 2005; Zheng and Poo, 2007). In support of this, soma translocation of migrating GABAergic interneurons relies on the occurrence of non-symmetrical calcium signals, whereby larger Calcium transients were observed towards the direction of migration (Moya and Valdeolmillos, 2004). At least the stimulatory role of depolarizing GABA on interneuron migration was reported to rely on calcium-dependent mechanisms (Behar et al., 1999; Bortone and Polleux, 2009), while elevated KCC2 expression induces a negative regulation of the frequency of spontaneous intracellular calcium transients and turns GABA into a stop signal (Bortone and Polleux, 2009). This is in line with the observation of reduced interneuron motility upon chelating intracellular calcium (Inada et al., 2011). Thereby, the route of entry determines the effects calcium triggers (Ghosh and Greenberg, 1995; West et al., 2001). In addition to voltage-gated L-type calcium channels, calcium can enter the cell from the extracellular space through calciumpermeable NMDARs, AMPA and kainate glutamate receptors as well as serotonine (5-HT3R) receptors (Ghosh and Greenberg, 1995). Moreover, calcium can be 11

released from intracellular stores through second messenger signaling (Ghosh and Greenberg, 1995). Calcium transients can modulate the cytoskeleton organization through the activation of calcium-dependent kinases, like calcium-calmodulin kinases II or doublecortin (DCX)-like kinases (Koizumi et al., 2006; Kumada and Komuro, 2004), and shRNAmediated inactivation of DCX or the DCX-like kinase diminishes cortical interneuron migration (Friocourt et al., 2007). Moreover, elevated calcium levels activate Lis1dependet rho-kinases, which are involved in tethering microtubule ends to the cortical actin cytoskeleton (Kholmanskikh et al., 2006). In line with this, mutations in LIS1 and DCX are associated with human neocortical migration disorders (Gleeson and Walsh, 2000). Besides, calcium entry into neurons triggers activity-dependent transcriptional responses, which are beginning to be approached for developing cortical interneurons. Serotonin-dependent stimulation of calcium activity in CGE-derived interneurons was shown to induce transcriptional changes, particular of genes related to cytoskeletal dynamics and guidance of migrating neurons (Frazer et al., 2015). In response to activity similar immediate early response transcription factors (immediate early genes-IEGs) were found to be activated in excitatory neurons and immature MGE cells, the source of inhibitory interneurons (Spiegel et al., 2014). These include Fos, the neuronal PAS domain-containing protein 4 (Npas4) and the early growth response protein 1 (Egr1) (Spiegel et al., 2014). However, it appears that these IEGs initiate discrete transcriptional programs in the different neuronal subtypes, including late response genes (LRGs) acting downstream of the IEGs. Distinct sets of LRGs were shown to be initiated in SST, VIP and PV-positive interneurons and excitatory cortical cells, eliciting different effects on synaptic development (Mardinly et al., 2016; Spiegel et al., 2014). NPAS4 induces LRGs with opposing actions in excitatory versus inhibitory neurons through the association with particular genetic elements (Spiegel et al., 2014). Numerous activity-mediated genes that have been identified in cortical interneurons are involved in migration regulation. These include DLX1, NPAS1, the cell motility protein 1 (ELMO1) and the special AT-rich binding protein 1 (SATB1), which display a subtype and stage-specific expression (Cobos et al., 2007; De Marco Garcia et al., 2011; Denaxa et al., 2012). Together, these studies propose that signaling from 12

neurotransmitter receptors induce activity-dependent transcriptional programs through changes in calcium transients, which modulate the migration of cortical interneurons. However, which genes and pathways are triggered by the different neurotransmitter receptors, in the distinct interneuron subpopulations and at particular stages of development necessitates profound investigations.

Transcriptional networks directing cortical interneuron migration The previous paragraphs discussed evidence for the differential responsiveness of cortical interneuron subtypes towards neuronal activity and guidance cues during their migration due to the subset and stage-specific expression of neurotransmitter and guidance receptors triggering particular transcriptional changes. Hence, one crucial aspect in understanding these migratory processes is to reveal the transcriptional networks that drive cell identity and migration of the diverse interneuron subsets, as they appear as interconnected events. While on the one hand particular transcriptional networks in distinct interneuron subsets and at different developmental stages seem to instruct their proper migration, on the other hand environmental cues are suggested to shape interneuron identity. In support this, many genes directing migration also affect cell fate, which will be briefly discussed as follows, while I refer to other reviews for comprehensive information of the transcriptional network orchestrating cortical interneuron subtype-specification (Bandler et al., 2017; Hu et al., 2017; Wamsley and Fishell, 2017). The transcription factor LHX6, decisive for the migration of MGE-derived cortical interneurons (Alifragis et al., 2004; Liodis et al., 2007; Zhao et al., 2008) by regulating the expression of migration-related genes such as Cxcr7 and Arx (Vogt et al., 2014), additionally controls Sox6 expression, which is crucial for the fate-determination of MGE-derived cortical interneurons (Batista-Brito and Fishell, 2009). Besides regulating migration (Friocourt and Parnavelas, 2011), the LHX6 target gene Arx further determines the PV and SST cell fate (Vogt et al., 2014). The activitydependent transcription factor SATB1, which is also a target of LHX6, promotes the migration as well as the maturation of a particular interneuron subset, namely the SST-positive interneurons (Close et al., 2012; Denaxa et al., 2012). Upstream of Lhx6 and on top of the hierarchical cascade governing MGE-interneuron development is the Nkx-class homeobox transcription factor 2.1 (NKX2-1) (Sandberg et al., 2016). Although only briefly expressed in immature MGE-derived interneurons 13

fated for the cortex becoming down-regulated at post-mitotic level, NKX2-1 seems to be required to set up transcriptional programs directing the MGE fate as well as migration. Besides promoting the subtype-specific expression of guidance receptors that mediate directional migration (McKinsey et al., 2013; Nobrega-Pereira et al., 2008; van den Berghe et al., 2013), NKX2-1 determines MGE identity, as a misspecification to other fates occurs in its absence (Flandin et al., 2010). The down-regulation of NKX2-1 depends on ZEB2, which represents another example for the close connection between migration and cell fate regulation. Conditional deletion of Zeb2 causes defective migration and a switch to a striatal fate (McKinsey et al., 2013; van den Berghe et al., 2013). Besides promoting expression of MGE-specific genes like cMaf, Mafb and Cxcr7 (McKinsey et al., 2013), ZEB2 acts on directional migration through constraining expression levels of Unc5b in MGEderived cortical interneurons. In Loss of function mutants, interneurons fail to migrate to the cortex and stay in the subpallium switching to a striatal fate (McKinsey et al., 2013). Thereby, it is not clear whether ZEB2 acts as cell fate determining factor or whether the misguided migration non-cell autonomously converts the fate caused by different environmental cues. Support for the instructive function of cellular environment on interneuron migration and final differentiation, arouse from different studies (Brandao and Romcy-Pereira, 2015). Transplantation experiments initially provided evidence that interneuron layer distribution depends on the cortical environment (Valcanis and Tan, 2003). This was confirmed by Fezf2 knockout studies, revealing that the absence of subcerebral projection neurons and their replacement by callosal projection neurons causes abnormal lamination of interneurons and altered GABAergic inhibition (Lodato et al., 2011a). However, homotopic and heterotopic grafting experiments of MGE-derived cortical and hippocampal interneurons propose that the environmental influence seems to vary dependent on the interneuron subtypes (Quattrocolo et al., 2017). In contrast to the MGE interneuron subsets, comparatively little is still known about the transcriptional networks orchestrating CGE and POA-interneuron migration and maturation. COUP-TFII expression is required for the migration of CGE-derived interneurons along the caudal migratory stream (Kanatani et al., 2008), while COUPTFI is crucial for the migration of CGE interneurons along the LMS and MMS (Touzot et al., 2016). Moreover, inactivating COUP-TFI affects expression of SP8 and COUPTFII, both of which are involved in the migration of CGE interneurons (Touzot et al., 14

2016). In addition to migration regulation in CGE-derived cortical interneurons, COUP-TFI and TFII influences subtype and laminar identity of MGE-derived cortical interneurons (Hu et al., 2017; Lodato et al., 2011b). While COUP-TFI is proposed to control the balance between MGE- and CGE-derived cortical interneurons by acting on intermediate progenitor divisions (Lodato et al., 2011b), COUP-TFI and TFII repress the PV interneuron fate and promote the SST interneuron fate in MGE progenitors, partly by driving Sox6 expression (Hu et al., 2017). PROX1 is another transcription factor identified to be expressed in interneurons subsets from distinct sites of origin. While PROX1 affects the migration as well as the maturation of CGE-derived cortical interneurons (Miyoshi et al., 2015), it is further expressed in HMX3-derived Htr3a-positive POA interneurons that differentiate to neurogliaform cells (Niquille et al., 2018). Likewise, the CGE-enriched transcription factors SP8 and NR2F2 are expressed in these cells (Niquille et al., 2018). Though, nothing is known yet about their function in the development of POA-derived interneurons. Similarly, for other transcription factors that are used for lineage tracing of POA-derived interneurons like NKX6.2 and DBX1, labeling the dorsal versus ventral POA neuropepithelium, and the post-mitotically expressed transcription factor HMX3 (Flames et al., 2007; Gelman et al., 2011; Gelman et al., 2009), the functional contribution to interneuron specification and migration remains elusive. For LHX1, another member of the LIM-homeodomain protein family, which is selectively expressed in the POA domain, the role in POA interneuron migration was recently investigated. By modulating the expression levels of Epha4 and efnB3, LHX1 is involved in channeling a subset of POA-derived cortical interneurons along the superficial route (Symmank et al., 2018b). LHX1 promotes the expression of efnB3 and negatively acts on Epha4 expression in POA-derived interneurons, thereby directing their migration through the basal telencephalon. Moreover, a shift of POA-derived interneurons allocated towards deeper cortical layers was detected in adult Hmx3-Cre/Lhx1 knockout mice (Symmank et al., 2018b). Thereby it is not clear whether this is due to the changed migration along the deep route within the basal telencephalon, which could be predictive for the migratory route and distribution within the cortex, or to the setup of distinct transcriptional programs in the Lhx1deficient interneurons resulting in changed responses to guidance cues in the cortex at later stages (Symmank et al., 2018b).

15

Together, several studies provide evidence that interneuron subtype identity and migration are closely linked, whereby on the one hand cell fate seems instructive for migration, while on the other hand the environment experienced during migration also appears to shape cell fate modulating stage and subtype-related gene expression.

Epigenetic mechanisms of gene expression control One crucial question is, how such stage- and subtype-specific transcriptional cascades that direct the development and migration of cortical interneuron subsets and their discrete responsiveness towards activity are established and how do epigenetic mechanisms of gene regulation contribute? Epigenetic mechanisms of transcriptional and posttranscriptional regulation, including histone modifications, DNA-methylation and non-coding RNAs, very likely prime early cell identity on top of cell specific transcriptional programs. However, the knowledge about particular implications in cortical interneuron development is still fragmented. DNA methylations and histone modifications are achieved by combinatorial actions of different classes of histone and DNA-modifying enzymes, which can be classified as “readers”, “writers” or “erasers” due to their capacity to recognize, add or remove epigenetic marks, respectively (Pande, 2016; Torres and Fujimori, 2015; Zhang and Pradhan, 2014). Specific epigenetic marks in turn are able to recruit certain multiprotein complexes harboring distinct enzymatic activities, which amplifies their regulatory potential (Telese et al., 2013). DNA methylation is accomplished by DNA methyltransferases catalyzing the methylation of cytosines at the fifth carbon of the pyrimindine ring (5mC), which was initially thought as a persistent epigenetic mark due its stable chemical nature. DNA methylation was found to occur predominantly on cytosines that are followed by guanines (CpG). Moreover, non-CpG or CpH methylation (H refers to adenine, thymine or another cytosine) is prevalent in brain tissue as well as in human embryonic stem cells (Guo et al., 2014; Lee et al., 2017; Pinney, 2014). DNA methylation can lead to silencing or activation of transcription, dependent on the methylated genomic regions. Hypermethylation of CpG sites located in promoter or enhancer regions often leads to transcriptional repression (Chodavarapu et al., 2010; Lister et al., 2009), while gene body methylation can lead to transcriptional activation 16

(Yang et al., 2014). Methylated cytosines are also evident in intergenic regions that control the transcription of genes nearby (Jones, 2012). In neurons, alterations in CpH methylation were also found to correlate with transcriptional changes (Guo et al., 2014; Lister et al., 2013), emphasizing the gene regulatory potential of CpH methylation. In the developing and adult nervous system, DNA methylation is mainly performed by DNMT1, DNMT3a and DNMT3b (Jang et al., 2017). In dividing progenitors, DNMT1 acts as maintenance enzyme due to its high affinity to hemimethylated DNA, while DNMT3a and DNMT3b were described as de novo methyltransferases (Jin and Robertson, 2013). However, in non-dividing post-mitotic neurons they seem to exert partly redundant functions (Feng et al., 2010). The discovery of active ways of DNA demethylation by Ten-eleven translocation (TET) family enzyme- dependent mechanisms (Wu and Zhang, 2017) opened the way to reconsider the functional implications of DNA methylation in post-mitotic and differentiated neurons. In the central nervous system, the DNA methylation landscape is dynamically changed during the developmental time course (Lister et al., 2013; Lister and Mukamel, 2015), which has been associated with cell-type specific development and maturation (Lister et al., 2013; Lister and Mukamel, 2015; Mo et al., 2015; Sharma et al., 2016). Moreover, DNMT-mediated DNA methylation seems to be implicated in synaptic plasticity and memory formation in the adult brain (Kennedy and Sweatt, 2016; Meadows et al., 2015; Meadows et al., 2016; Sweatt, 2016; Zovkic et al., 2013). In addition to modifications of the DNA, epigenetic transcriptional regulation can be achieved by post-translational modifications of N-terminal histone residues, thereby altering the accessibility of the DNA to the regulatory transcriptional machinery (Bannister and Kouzarides, 2011). These modifications comprise of histone acetylation and deacetylation by histone acetyltransferases (HATs) and histone deacetylases (HDACs), phosphorylation and dephosphorylation by kinases and phosphatases, and methylation/demethylations of lysine and arginine side chains by histone methylases and demethylases (Bannister and Kouzarides, 2011). Further ways of histone modifications include deimination, ubiquitylation, sumoylation, ADP ribosylation,

modifications

of

threonine

or

serine

side

chains

with

β-N-

acetylglucosamine sugar residues, histone tail clipping and histone proline isomerization (Bannister and Kouzarides, 2011). The potential for transcriptional 17

control was shown for diverse histone modifications, which is achieved either by changing the overall chromatin structure (condensation/decondensation) or by affecting the binding of effector molecules (Bannister and Kouzarides, 2011). It is already clear that DNA methylation and histone modifications can no longer be considered unconnected processes. The question on how DNMTs, especially in nondividing cells, recognize their target sequence lead to the discovery of DNMTs recruitment by chromatin marks (reviewed in (Ravichandran et al., 2017). In conjunction, methylcytosine-binding proteins can recruit histone deacetylases to methylated DNA sequences (Jones et al., 1998; Nan et al., 1998). In addition to providing support for target recognition, recent studies revealed that there are direct interactions between DNA-methylating and histone-modifying enzymes via specific binding domains (Clements et al., 2012; Smallwood et al., 2007; Vire et al., 2006). Beyond DNA methylation and histone tail modifications, non-coding RNAs (ncRNAs) act as epigenetic modifiers of gene expression (Peschansky and Wahlestedt, 2014). ncRNAs can be classified into short ncRNA with less than 200 nucleotides in length, while larger transcripts are regarded as long ncRNA (lncRNA). Short ncRNAs include miRNAs, which are 20–23 nucleotides (nts) in length and recognize target mRNAs by complementary binding to a 2–7 nt long seed region in the 3´-UTR (Bartel, 2009; Fabian and Sonenberg, 2012) or 5´-UTR (Zhou et al., 2009). This activates the miRNA-induced silencing complex (miRISC), which includes the endoribonuclease DICER that cleaves double-stranded RNA. DICER is further involved in the formation of another class of short ncRNAs, the endogenous siRNAs (endo-siRNAs), by cleaving long double-stranded ncRNAs. These are formed from natural senseantisense transcript pairs (cis-nat siRNAs) at a single locus, from gene-pseudogene pairs (trans-nat siRNAs) or from hairpin loops formed at inverted repeat-containing sequences (Rother and Meister, 2011; Watanabe et al., 2008). In contrast to miRNAs, endo-siRNAs seem to require extensive sequence complementarity to induce gene repression (Okamura et al., 2008). Both types of short ncRNAs act as posttranscriptional repressors of gene expression (Peschansky and Wahlestedt, 2014).

Epigenetic regulation of cortical interneuron development and migration Although numerous studies provide evidence for crucial functions of epigenetic mechanisms

of

transcriptional

and

posttranscriptional

regulation

in 18

neurodevelopmental processes (Adefuin et al., 2014), the knowledge about particular implications in the diverse aspects of cortical interneuron development is still in its infancies. However, neuronal activity is known to shape the epigenetic landscape (Guo et al., 2011; Spiegel et al., 2014), and several of the transcription factors described to direct cortical interneuron development also affect the epigenome. NKX2-1 conditional knockout animals display significant alterations in histone profiles (Sandberg et al., 2016) and Zeb2 knockout in human embryonic stem cells leads to a de-richment of genes associated to the epigenome, such as histone modification and chromatin organization

(Stryjewska et al., 2017). Moreover, SATB1 recruits chromatin

remodeling factors to control gene transcription (Cai et al., 2006) For MGE interneurons, a crucial role for chromatin remodeling through ARID1B, a component of the human BRG1/BRM associated factor chromatin remodeling complex that exerts gene expression control by facilitating DNA access for transcription factors (Ronan et al., 2013), was recently described (Jung et al., 2017). Arid1b haploinsufficient mice display augmented cell death of MGE progenitors leading to reduced numbers of cortical interneurons. In addition, a defective interneuron morphology, synapse structure and inhibitory neurotransmission was observed in adult cortices (Jung et al., 2017). The authors revealed a transcriptionpromoting function of ARID1B through the modulation of physical access of histone modifiers, thereby creating a favorable chromatin environment. In detail, ARID1B is proposed to bridge histone acetyltransferases with histone 3 through which lysine 9 acetylation at histone 3 (H3K9ac) is facilitated, representing an activating histone mark (Jung et al., 2017). This seems to affect the transcription of cortical interneuronspecific genes like Pvalb, Gad1 and Slc32a1 (Jung et al., 2017). However, the role of histone modifications in cortical interneuron migration remains unknown so far. Similar to histone modifiers, the role of DNA methylation in interneuron development, particular in regard to interneuron migration, is just beginning to be approached. The regulation of DNMT expression and function in developing cortical interneurons seems critical, as prenatal stress elevates Dnmt1 and Dnmt3a expression and induces abnormalities in the DNA methylation network as well as behaviors indicative of a schizophrenia-like phenotype in offspring (Matrisciano et al., 2013). Hence, revealing their detailed function appears crucial in the context of GABAergic interneuron-related diseases. 19

DNMTs are widely expressed in neuronal precursors of the central nervous system (Feng et al., 2005) including cortical interneuron progenitors (Pensold et al., 2016). In the spinal cord, Dnmt1 deficiency at progenitor level causes precocious astroglial differentiation and hypomethylation of genes associated to the gliogenic JAK/STAT pathway (Fan et al., 2005). Likewise, Dnmt1-deficiency promotes the differentiation of neuronal stem cells into astrocytes in precursors of the dendate gyrus (Noguchi et al., 2016). Hence, DNMT1 function seems critical in neuronal progenitors of the central nervous system, driving the neuronal fate by inhibiting astroglial differentiation during the neurogenic period. Whether DNMTs exert similar functions in progenitors of the basal telencephalon, where cortical interneurons arise, remains to be elucidated. The functional implication of DNMT1 in the migration of cortical interneurons was investigated for POA-derived cells by inducing Dnmt1 deletion at post-mitotic level in Hmx3-positive cells (Pensold et al., 2016). The Hmx3 population of the POA mainly gives rise to inhibitory interneurons including neurogliaform cells and glia cells fated for the cerebral cortex, but also to cells destined for other telencephalic structures (Gelman et al., 2009; Niquille et al., 2018; Pensold et al., 2016). Dnmt1 deletion in post-mitotic Hmx3 cells induced morphological abnormalities and a loss of the stereotyped migratory morphology accompanied by migratory defects and elevated rates of cell death, leading to reduced numbers of NPY-expressing cortical interneurons in adult mice (Pensold et al., 2016). In line with these findings, DNMT1 promotes the morphological development and migration of dendate gyrus neurons (Noguchi et al., 2016) as well as the morphological maturation of cortical projection neurons (Hutnick et al., 2009). Together these studies suggest that DNMT1 acts on neuronal migration by controlling the expression of cytoskeleton-related genes. As a target gene of repressive DNMT1 transcriptional activity involved in the regulation of the cell morphology in migrating POA-derived interneurons, Pak6, coding for a p21-activated kinase, was identified (Pensold et al., 2016). Similar to Pak6, the DNMT1-dependent transcriptional repression of a high proportion of genes seemed not be mediated by DNA methylation (Symmank et al., 2018a), pointing to non-canonical actions executed by DNMT1 in migrating cortical interneurons. Indeed, in non-neuronal cells DNMTs were described to influence transcription through interactions with histone modifications (Du et al., 2015). In addition to recruiting histone deacetylases to methylated DNA sequences by methylcytosinebinding 20

proteins (Jones et al., 1998; Nan et al., 1998), direct interactions between DNA methylating and histone modifying enzymes via specific binding domains were shown to influence histone methylation (Clements et al., 2012; Smallwood et al., 2007; Vire et al., 2006). DNMT1 in particular was reported to interact with EZH2 (Ning et al., 2015; Purkait et al., 2016; Vire et al., 2006), the core enzyme of the polycomp repressor complex 2 mediating repressive trimethylations on lysine 27 of histone 3 (H3K27me3) (Margueron and Reinberg, 2011). Moreover, DNMT1 affects H3K27 trimethylation through transcriptional changes of Ezh2 expression (Purkait et al., 2016; So et al., 2011), while EZH2 in turn recruits DNMT1 to polycomp target genes (Ning et al., 2015; Vire et al., 2006). In POA-derived interneurons, DNMT1 modulates global H3K4me3 and H3K27me3 levels, associated with permissive and repressive transcription, respectively (Symmank et al., 2018a). In regard to Pak6 expression, evidence was found for a DNMT1/EZH2 protein interaction-dependent modulation of H3K27me3 marks in regulatory regions of the Pak6 gene locus (Symmank et al., 2018a). Inhibiting EZH2 results in a comparable up-regulation of Pak6 expression and in morphological changes reminiscent to what was observed upon Dnmt1 deletion (Pensold et al., 2016; Symmank et al., 2018a). Depleting Pak6 expression levels rescued the morphological defects induced by EZH2 inhibition, similar to the rescue that was obtained in Dnmt1-deficient POA-interneurons upon Pak6 siRNA application (Pensold et al., 2016). Hence, in immature POA-derived cortical interneurons, DNMT1 acts on transcription through interactions with histone modifying enzymes, thereby modulating their migratory morphology. Beyond DNMT1 function, the relevance of miRNAs in interneuron development was investigated by Tuncdemir and colleagues (Tuncdemir et al., 2015) exploiting a DICER knockout mouse model. As proliferation was not affected and miRNAs were found selectively enriched in post-mitotic MGE-derived cells, the authors emphasize the importance of miRNA-based epigenetic remodeling in the post-mitotic maturation and migration of cortical interneurons (Tuncdemir et al., 2015). Indeed, deletion of Dicer caused impaired migration and increased apoptosis culminating in reduced numbers of MGE-derived interneurons in the adult cortex (Tuncdemir et al., 2015). Moreover, in DICER mutants, about half of the MGE-derived interneurons fail to express subset-specific markers and display morphological aberrations, whereby PVinterneurons are more strongly affected. Microarray analysis revealed that Dicerdeficient E15.5 cortical interneurons extracted from the cortex show an altered 21

expression of cytoskeleton and apoptosis-related genes. Moreover, they precociously express genes related to their mature identity (Tuncdemir et al., 2015). Additionally, the expression of the transcription factor Ebf1, enriched in LGE-derived striatal interneurons driving their differentiation and migration (Garcia-Dominguez et al., 2003; Garel et al., 1999), was also elevated in Dicer-deficient cortical interneurons (Tuncdemir et al., 2015). Hence, in contrast to the deletion of Dnmt1, which similarly caused an altered morphology, migratory defects and increased apoptosis (Pensold et al., 2016; Symmank et al., 2018a), the absence of miRNAs additionally affects cell fate (Tuncdemir et al., 2015).

Conclusions: Together, the studies reviewed in this article propose that migration relies on a facetrich repertoire of regulatory instances including neuronal activity, transcriptional as well as epigenetic networks. It is becoming increasingly clear that cell fate and migration do not represent independent events. Subtype and stage-specific transcriptional

cascades

drive

the

expression

of

particular

guidance

and

neurotransmitter receptors, which seem to cause differential responsiveness towards neurotransmitters and guidance cues. In turn, the environmental information confronted with during migration appears likewise relevant for cell fate determination. Although initial work was published on the role of epigenetic mechanisms of gene regulation in regulating cortical interneuron development, migration and cell fate, a lot of work still needs to be done to dissect the detailed mechanisms and to draw a conclusive picture. Many aspects remain an open question. What is the role of epigenetic traits in setting subtype-specific transcriptional cascades at early postmitotic precursor or basal progenitor level? To what extent is the epigenetic machinery affected by neurotransmitter receptor signaling during migration and helps to integrate and respond to environmental information? And how does neuronal activity in turn affects the epigenetic machinery in migrating cortical interneurons? To connect these different lines of research might be a promising way to answer crucial still unsolved questions of how the cortical GABAergic system is established.

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Highlights 

Summarizes recent research on the regulation of cortical interneuron development with focus on migration

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Reviews the role of neuronal activity and the implications of epigenetic regulation in controlling cortical interneuron migration

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Proposes an integration of both aspects, activity and epigenetics, for future research on interneuron development

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