Abstract
In the last three decades it became evident that the GABAergic system plays an essential role for the development of the central nervous system, by influencing the proliferation of neuronal precursors, neuronal migration and differentiation, as well as by controlling early activity patterns and thus formation of neuronal networks. GABA controls neuronal development via depolarizing membrane responses upon activation of ionotropic GABA receptors. However, many of these effects occur before the onset of synaptic GABAergic activity and thus require the presence of extrasynaptic tonic currents in neuronal precursors and immature neurons. This review summarizes our current knowledge about the role of tonic GABAergic currents during early brain development. In this review we compare the temporal sequence of the expression and functional relevance of different GABA receptor subunits, GABA synthesizing enzymes and GABA transporters. We also refer to other possible endogenous agonists of GABAA receptors. In addition, we describe functional consequences mediated by the GABAergic system during early developmental periods and discuss current models about the origin of extrasynaptic GABA and/or other endogenous GABAergic agonists during early developmental states. Finally, we present evidence that tonic GABAergic activity is also critically involved in the generation of physiological as well as pathophysiological activity patterns before and after the establishment of functional GABAergic synaptic connections.
The GABAergic system is critically involved in neuronal development (e.g., ; ; Wang and Kriegstein, 2009; ), influencing virtually all developmental steps from neurogenesis () to the establishment of neuronal connectivity (Wang and Kriegstein, 2008). Since many of these events occur before the onset of synaptogenesis, a tonic, extrasynaptic GABAergic transmission may be important. In the following sections we will first describe the development of the GABAergic system, with special emphasize on all elements that support the particular role of extrasynaptic transmission. Subsequently, we will describe the influence of GABA on various developmental events and present evidence for a critical role of non-synaptic signaling in these processes. In addition, we will summarize observations that demonstrate an important role of extrasynaptic GABAergic transmission in the developing brain after the formation of GABAergic synapses and after onset of GABAergic synaptic transmission. And finally, we like to discuss the origin and nature of additional endogenous GABAergic agonists that mediate extrasynaptic effects during development.
Most studies mentioned in this review describe the development and influence of the GABAergic system during prenatal phases and the first postnatal week in rodents. This period is to some extent comparable to prenatal development in humans (), although a general comparison of pre- and perinatal stages between rodents and humans is complicated due the relatively advanced human brain development and the complex expansion pattern of different cortical areas during onto- and phylogenesis (; ). In addition, we like to emphasize that substantial developmental progress occurs during the first postnatal week in rodents and that at one given day of early development, neurons in different cortical regions and layers differ by 2–3 days in their developmental stage.
DEVELOPMENT OF EXTRASYNAPTIC AND SYNAPTIC GABAergic TRANSMISSION
Cells in the developing nervous system respond to GABA at surprisingly early stages. The first evidence for this has been found in dissociated cells from the earliest phases of neurogenesis in the turtle brain, which show bicuculline sensitive responses upon GABA application (Shen et al., 1988). In rodents neuronal progenitors in the ventricular zone at embryonic day (E) 15 (; ) as well as postmitotic migrating neurons () already reliably show GABAergic responses (Figure 1). In accordance with this early onset of GABAergic responses, the expression of GABAA receptors also starts during very early brain development.
FIGURE 1
GABAA receptors are heteropentameric molecules composed of 19 possible subunits (α1–6, β1–3, γ1–3, δ, ε, φ, π, and ρ–3). The subunit composition determines GABA affinity, channel conductance and kinetics, pharmacology and subcellular localization of the receptors (). A few functional consequences of subtype compositions relevant for this review are (i) in particular the γ2 subunit determines the synaptic allocation of GABAA receptors, while δ subunit containing receptors are exclusively located at extrasynaptic sites, (ii) α4–6 and ρ subunit containing receptors have been found predominantly at extrasynaptic localizations, while α1–3 containing receptors are supposed to constitute the synaptic GABAA receptors, and (iii) δ subunit and ρ subunit containing receptors typically reveal a high GABA affinity and a slow and incomplete desensitization, appropriate for a tonic activation by interstitial GABA (reviewed in ; ).
In situ hybridization experiments in the neocortex revealed expression of GABAA receptors as early as at E13 with the appearance of β3 subunits in the neuroepithelium (). At E14/E15 α3, α4 are expressed in the developing cortical layers (; ). Between E15 and E17 γ2 subunit mRNA is detected in the neocortex, with the highest expression levels in the cortical plate (CP; ; ; Van Eden et al., 1995). At E17 there is evidence that even α6 subunits, which are in the adult brain nearly exclusively located in the cerebellum (), are expressed in the cortical neuroepithelium (). In contrast, the α1 subunits characteristic for many mature GABAA receptors are expressed relatively late between E19 and P0 (; Van Eden et al., 1995), while δ subunit expression is observed only postnatally (). These observations are supported by northern blot analyses which reveal expression of α2 and α4 at E18 in total brain homogenates, while α1 expression starts only after birth (). On the other hand, for precursors of GABAergic interneurons traveling from the lateral ganglionic eminence to the cerebral cortex a stringent up-regulation of α1 and γ1–3 subunits occurs after they enter the cortex, which is directly linked to an increase of GABA affinity (). To our knowledge no study has been published for rodents that investigated the prenatal appearance of different GABAA receptor subunits on protein level. However, in rodents at the day of birth (P0) an intense α2 receptor immunoreactivity has been observed in the neocortex, while α1 receptors immunoreactivity is low, but detectable (). In the primate neocortex a significant expression of α2, α4, and α5 was observed during prenatal development (; ), while α1 subunits appear shortly before birth and are substantially up-regulated in the first postnatal year ().
In the rodent hippocampus expression of mRNA for α2 and α5, but also γ2 subunits start at E15, while δ subunit mRNA was detected only after birth (; ; ). At E19 it has been found that neuroepithelial cells or early postmitotic cells in the hippocampus express predominantly α4 and α5 containing GABAA receptors (). Expression of α1 subunit mRNA appear only postnatally (; ). Immunohistochemical studies in the perinatal hippocampus revealed a nearly absence of α1 subunits, while α2 subunits were highly abundant ().
Ionotropic GABA receptors constituted of ρ subunits (also termed GABAC receptors) have a high GABA affinity, slow activation and inactivation kinetics and show little desensitization (). In accordance with these properties, they can mediate extrasynaptic GABAergic effects (). Expression of ρ subunits has been found in lower neocortical layers of the E15 mouse brain () and in the early postnatal hippocampus (Rozzo et al., 2002). In accordance with the early expression of ρ subunits only in lower neocortical layers, functional ρ subunit containing GABAA receptors are detected in the intermediate zone (IZ), while they are not expressed in the CP (; Figure 2). The pharmacological properties of these receptors indicate that they most probably are ρ subunits containing heteropentamers, as has been also suggested for interneurons in the adult hippocampus and juvenile CA1 pyramidal neurons (Semyanov and Kullmann, 2002; ).
FIGURE 2
In summary, these studies demonstrate that in the cerebral cortex and hippocampus classical GABAA and ρ subunit containing GABA receptors are expressed at early developmental stages, and that these receptors probably contain α2–α5 and ρ, but also γ2 subunits. Although the expression of γ2 subunits typically corresponds to a postsynaptic localization of GABAA receptors, the relatively high expression levels of α4/α5 and ρ subunits are compatible with extrasynaptic GABAA receptors. In contrast, there is compelling evidence that δ subunits, which are typical for classical extrasynaptic receptors in the immature brain (), are lacking during early embryonic development.
During embryonic and early postnatal development ionotropic GABA receptors mediate in pyramidal neurons depolarizing membrane responses (; ; ; ; ; Valeeva et al., 2013). These depolarizing GABAergic responses are caused by Cl- efflux via GABAA receptors due to the high intracellular Cl- concentration in developing neurons (), and play an essential role for the trophic actions of GABA during early development (; ; Wang and Kriegstein, 2009; ; but see ). In GABAergic interneurons GABAA receptor activation mediate comparable, slightly depolarizing actions in interneurons during early postnatal stages as well as in the adult brain ().
In addition to ionotropic GABA receptors, metabotropic GABAB receptors are also important elements of the immature GABAergic system. Functional GABAB receptors are heterodimers consisting of GABAB1R and GABAB2R subunits and are mainly located distant to release sites, suggesting an extrasynaptic activation (Ulrich and Bettler, 2007). A co-localized protein expression of both GABAB receptor subunits, and thus presumably also functional GABAB receptors, has been found in hippocampal and cortical regions after E15 (; ; ). Accordingly, evidence for a functional implication of GABAB receptors on different developmental events has been demonstrated in the immature neocortex and hippocampus (; ; ; ). In the first postnatal week a reliable presynaptic effect of GABAB receptors is observed in the rodent neocortex and hippocampus, while a postsynaptic current is less developed (; ; ).
A peculiar observation of the in situ hybridization studies for GABAA receptor subunits was the early expression of γ2 subunits, which are implicated in synaptic clustering of GABAA receptors, during early embryonic stages. However, γ2 subunits mediate the postsynaptic clustering of GABAA receptors via an interaction with the scaffolding proteins gephyrin and collybistin (; ). While gephyrin is expressed at high levels in the neuroepithelium already at E14, collybistin expression was observed in the cortical anlage only in regions with postmitotic neurons, which strongly suggests that GABAA receptors cannot form postsynaptic clusters in the ventricular and subventricular zones and on migrating neurons (; ).
GABA required for the activation of these GABA receptors can originate either from GABAergic neurons or GABAergic fibers. GABAergic interneurons are generated in rodents mainly in the medial and caudal ganglionic eminence and migrate tangentially to the neocortex and hippocampus (; ; ), where they, depending on their origin, differentiate in the diverse types of GABAergic interneurons (Tricoire et al., 2011). In the human neocortex a substantial fraction of the GABAergic interneurons is, however, generated in the ventricular zone of the dorsal pallium (; Yu and Zecevic, 2011). The first GABA positive neurons are detectable in the primordial plexiform layer of the cortical anlage already at E12 (). In subsequent embryonic stages GABAergic neurons are abundant in all layers of the developing cortex between the marginal zone and the subventricular zone (; Van Eden et al., 1989; ; ). In the human neocortex the first GABAergic neurons were detected at gestational week 6.5 even before the appearance of the CP (Zecevic and Milosevic, 1997). In the rodent hippocampus GABAergic interneurons were first detected between E14 and E16 in the inner marginal zone, the subplate and the subventricular zone (Soriano et al., 1994; ). In addition to this early appearance of GABAergic neurons, a dense network of GABAergic fibers originating from extracortical regions reach the cortical anlage during these early embryonal stages even before the appearance of GABAergic neurons (; ; ).
GABA is mainly produced by the glutamic acid decarboxylases (GAD), which is expressed in two major isoforms. GAD-65 is considered to mediate the production of GABA intended for synaptic release, while GAD-67 is supposed to maintain cytoplasmic GABA levels (Soghomonian and Martin, 1998). In the rodent neocortex expression of GAD-67 is detectable at E15 () in the germinal zone of the cortical anlage, while GAD-65 occurs delayed and is observable only after P6 (). In the hippocampus both GAD-65 and GAD-67 protein could be detected at E18, with both isoforms expressed mainly at somatic locations during prenatal development (). Expression of GAD has also been found in fetal human brain before gestational week 15 (), when GAD-67 is the prominent isoform (). Thus in particular a somatic generation of GABA can appear during early stages of corticogenesis. In contrast, the GABA degrading enzymes GABA transaminase and succinate semialdehyde dehydrogenase reveal low expression levels in the pre- and early postnatal rodent neocortex (; ), suggesting that a substantial portion of GABA is distributed within the CNS via the interstitium.
For synaptic release GABA must be accumulated in transmitter vesicles by the vesicular inhibitory amino acid transporter (vIAAT) or vesicular GABA transporter (vGAT; Wojcik et al., 2006). At P0 the expression of vGAT in the neocortex is rather low and mostly restricted to fibers (). In the rodent hippocampus GABAergic inputs were observed before birth in about 75% of pyramidal neurons at P0 and in 65% of interneurons (Tyzio et al., 1999; ), indicating the early appearance of functional GABAergic synapses, but also that synaptic spillover may be a source of extrasynaptic GABA receptor activation. No GABAergic synaptic responses were observed in proliferative regions of the cerebral cortex (). On the other hand, reliable tonic GABAergic currents were found in the embryonic neocortical neurons in the ventricular zone () and the CP (), and in neuronal cultures of embryonic hippocampal neurons (Valeyev et al., 1998). These observations indicate that GABAergic responses precede synaptic GABAergic transmission, strongly suggesting that non-synaptic transmission plays an important role during prenatal development. Indeed, there is compelling evidence that during these stages a substantial part of basal, but also of stimulated GABAergic transmission occur via non-vesicular release (). The tonic GABAergic currents observed in neuronal cultures of embryonic hippocampal neurons suggest that hippocampal neurons itself can be a source of GABA in these cells (Valeyev et al., 1998). Subsequent in vitro experiments revealed that isolated neurons from the CP can release GABA in sufficient large amounts to obtain micromolar concentrations in the supernatant (). In immature neocortical slices an extracellular GABA concentration of 250–500 nM, and thus sufficiently high to activate high affinity ionotropic GABA receptors or GABAB receptors has been found (; ).
Possible candidates for a non-vesicular GABA release are GABA transporters (GATs). In the adult nervous system these transporters mediate the uptake of GABA from interstitial space, show mainly a neuronal localization of the GAT-1 isoform and mainly glial localization of GAT-3 isoform (). Accordingly these two subtypes are responsible for controlling extracellular GABA from vesicular and non-vesicular sources, respectively (Song et al., 2013). However, these transporters can also act in reverse mode and thus release GABA from cells (; ). In particular the high intracellular Cl- concentration in immature neurons, which directly influences GAT mediated GABA transport by determining the reversal potential of this Cl- dependent transmembrane transporter, can result in less efficient uptake or even a reversal of the transport mode (). In the mouse brain GAT-1 expression starts at E14 in the medial ganglionic eminence and is detected at E16 in the neocortical subventricular zone (). GAT-3 is already expressed in the neocortical subventricular zone at E14 (). In contrast, in the developing hippocampus GAT-1 expression is low at early postnatal age, with GAT-3 expression dominating (). Interestingly, between the end of the first postnatal week and the end of the first postnatal month a transient somatic location of GAT-1 expression has been demonstrated in the rat neocortex and hippocampus (Yan et al., 1997). In addition, in the immature rat cortex GAT-1 is abundant in astrocytes and GAT-3 in neurons (Yan et al., 1997; ), despite the mainly neuronal localization of GAT-1 and the mainly glial localization of GAT-3 in the adult CNS (; ). Both observations suggest a substantial shift in the functional role of GAT during development. A direct implication of GAT-1 for GABA release has been demonstrated in tangentially migrating precursors of GABAergic interneurons (), where glutamatergic activation leads to a non-vesicular GABA release by a Na+-increase driven reversal of the GAT-1 transporter (). On the other hand, in cortical neuroblasts the activity dependent GABA release does not depend on GATs (), indicating that additional, currently unknown pathways may contribute to non-vesicular GABA release during early development. And finally, it has been shown for the early postnatal hippocampus and neocortex that GAT-1 is already effectively removing GABA from the extracellular space and thereby directly regulates tonic GABAergic currents and affects intrinsic neuronal activity (Sipila et al., 2004, 2007; ).
Overall, these studies suggest that in the immature neocortex and hippocampus all essential elements for functional GABAergic transmission appear at very early stages, while the elements for reliable synaptic GABA release and GABAA receptor clustering occur at later developmental stages. In summary, these findings indicate that activation of extrasynaptic GABAergic receptors underlies the diverse trophic actions of GABA during early neuronal development.
INFLUENCE OF EXTRASYNAPTIC GABAergic TRANSMISSION ON CRITICAL EVENTS DURING PRE- AND EARLY POSTNATAL DEVELOPMENT
GABA has been considered as a major neurotrophic factor during embryonic development (Varju et al., 2001; ; ; Wang and Kriegstein, 2009). Different developmental events, ranging from proliferation to the establishment of mature synaptic circuits depend on GABA, with a substantial portion of these events occurring without a major contribution of synaptic processes.
Application of GABAergic agonists increases DNA synthesis and the proliferation of neuroblasts in the ventricular zone, whereas it decreases proliferation in the subventricular zone (; ). Most probably the majority of these neuronal progenitors in the ventricular zone are radial glial cells (), on which functional GABAA receptors have been reported (). While alterations in proliferation induced by the external GABA application demonstrate that GABA has the potential to directly interfere with neurogenesis, the observation that inhibition of GABAA receptors induces the opposite effect clearly shows that endogenously released GABA regulates neurogenesis in ventricular and subventricular zones (; ). In addition to GABAA receptors, it has been also shown that GABAB receptors are involved in controlling neurogenesis () and gliogenesis (). It can be assumed that extrasynaptic GABAergic transmission influences these processes, since in both layers synaptic GABA release has not been reported so far. This mechanism has been documented in adult neurogenesis, where GABAergic neuroblasts in the subventricular zone release GABA via non-vesicular mechanisms, which in turn impede the proliferative activity of glia-derived progenitor cells (). In addition, it could be shown that during adult neurogenesis α4 subunit containing GABA receptors are involved in the regulation of neurogenesis (), which also suggests that extrasynaptic transmission is essential. Neurogenesis in the neocortex is also impeded by glutamate, and this glutamatergic inhibition of proliferation of glutamatergic pyramidal neurons is supposed to serve as a feedback mechanism to control the number of excitatory neurons (Wang and Kriegstein, 2009). However, because in rodents the ventricular and subventricular zones of the cortical anlage do not give rise to GABAergic interneurons, the functional role of GABAergic control of proliferation is probably more complicated.
In the mammalian brain the neurotransmitter phenotype of neurons is determined by different transcription factors and is normally established with neurogenesis (). The observation that granule cells of the dentate gyrus can switch their neurotransmitter phenotype in an activity dependent manner (), suggest that during neuronal development the expression of transcription factors may also be affected by neurotransmitters and their receptors. In the central nervous system of Xenopus it has already been shown that GABA can directly influence neurotransmitter specification via GABAB receptors (Root et al., 2008), however, for mammalian species it has not been demonstrated yet whether GABA receptors can influence the neurotransmitter phenotype.
A variety of in vitro and in vivo studies reported that GABA is an important determinant of neuronal migration, acting as chemoattractant, regulating cell mobility and influencing initiation and termination of the migration process (; ; ). A selective inhibition of GABAA receptors enhances radial migration in neocortical organotypic slice cultures (; ) and in vivo induces severe cortical malformations leading to upper cortical heterotopia (), suggesting that GABAA receptors provide a stop signal for migrating neurons (Figure 3A). In contrast, specific inhibition of ρ subunit containing GABAA receptors or a simultaneous inhibition of both subclasses of GABAA receptors impedes radial migration (; ), suggesting that ρ subunit containing GABAA receptors support the migration out of deeper cortical layers (Figure 3B). Functional ρ subunit containing GABAA receptors are only found in the subcortical regions of the developing cortex that lack evidence for synaptic release (), indicating that they are predominantly activated by non-synaptically released GABA. Since so far no synaptic inputs on migrating neurons have been demonstrated, it has been suggested that the stop signal for migrating neurons is mediated by the higher interstitial GABA concentrations in superficial layers of the developing cortex (). Despite the different effects of both subclasses of GABAA receptors on radial migration, the effect of ionotropic GABA receptors on migration is most probably mediated by depolarization-induced Ca2+ transients, which are essential for the induction and maintenance of radial migration (, but see ). In addition, it has been demonstrated that GABA facilitates the tangential migration of GABAergic interneurons to the appropriate neocortical locations via GABAA receptors (; ). Metabotropic GABAB receptors stimulate the transition of radially migrating neurons from the IZ to the CP () and mediate the migration of interneurons to their appropriate locations in the neocortex during embryonic stages (). In the immature hippocampus GABAA receptors promote radial migration (). Importantly, neuronal migration is unaffected in animals in which the synaptic release is completely suppressed (), again emphasizing the essential role of non-synaptically released GABA acting on extrasynaptic receptors for neuronal migration in the hippocampus.
FIGURE 3
GABA also exerts a direct effect on neurite growth and axon elongation (see Sernagor et al., 2010 for review). A variety of studies demonstrated that GABA application promotes the outgrowth and ramification of dendrites in neocortical and hippocampal neurons (e.g., ; ). This dendrite promoting effect of GABA relies on depolarizing GABAergic responses and subsequent Ca2+ signals (; ; Wang and Kriegstein, 2008). Dendritic ramification is inhibited by GABAergic antagonists (), indicating that endogenous GABA is required for normal neurite formation. The cell culture studies of convincingly showed that not only blocking GABAA receptors, but also inhibition of GAD severely impairs dendrite formation, which strongly suggests that an autocrine release of GABA acting on extrasynaptic GABAA receptors is required for this effect. In cell cultures from embryonic cortical neurons axonal growth is also accelerated by GABAA receptor activation via Ca2+ and calmodulin-dependent kinase 1 activation (). Since this effect is reversed by GABAA receptor antagonists and axon extension partly occurs before the appearance of synaptic GABA release, it has been suggested that tonic GABAergic effects also contribute to the facilitating GABA effect on axon extension (Sernagor et al., 2010). Activation of presynaptic GABAB receptors is required to stabilize developing GABAergic synapses of basket cells in the mouse occipital neocortex (). On the other hand, it has been shown that already in the immature hippocampus and neocortex tonic activation of presynaptic GABAB receptors reduces GABA release (Safiulina and Cherubini, 2009; ).
Subsequent developmental events are also directly influenced by GABAergic signaling. For example it has been shown that depolarizing GABAergic responses are essential for synaptogenesis (Wang and Kriegstein, 2008). But because these events occur mostly after the onset of synaptogenesis and after the functional expression of GABAergic synaptic inputs (e.g., ; Tyzio et al., 1999; ; ), synaptic GABAergic effects may dominate these events. However, it has been shown that this GABAergic influence on synaptogenesis is closely linked to N-methyl-D-aspartate (NMDA) receptors (Wang and Kriegstein, 2008). In immature neurons the Mg2+ block from NMDA receptors is released by an GABAergic depolarization before 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) mediated synaptic inputs appear (), leading to spontaneous correlated network activity, which is typical for the developing brain (; ; ) and which probably plays an essential role for the maturation of neuronal networks (see ; ; for review). But since tonic GABAergic currents are essential to drive such events in the immature hippocampus (Sipila et al., 2005), it can be assumed that tonic GABAergic currents continue to contribute to the trophic GABA action even after the onset of GABAergic synaptic transmission.
In summary, these studies provide convincing evidence that tonic GABAergic currents control the genesis, migration and differentiation of neurons during early development. All these events occur either before the onset of synaptic GABAergic transmission or in neurons that do not receive synaptic inputs, indicating that extrasynaptic GABAergic signaling is essential for these processes. Beside this correlative indication, the studies by ; , and provide strong evidence for the important role of non-synaptically released GABA on neurogenesis, migration, and differentiation. An additional evidence for the dominating role of non-vesicular released GABA on cortical development is the observation that no anatomical abnormalities are detected in the neocortex of vGAT knockout mice, in which synaptic GABA release is absent (Wojcik et al., 2006). Similarly, a normal neocortical appearance, dendritic arborization and even synaptic structure has been described in perinatal mice after complete suppression of synaptic release in munc-18 knockout mice (Verhage et al., 2000; ), again emphasizing the role of non-vesicular release and extrasynaptic receptors for early neuronal development.
TONIC CURRENTS REGULATE EXCITATION AFTER GABAergic SYNAPTOGENESIS
Tonic GABAergic currents also strongly influence the activity of the immature nervous system after the onset of synaptic activity. As discussed above, in particular the different subunit composition of GABAA receptors or distinct distribution and transport modes of GATs can contribute to these age-dependent effects. For instance in the rodent hippocampus α5 subunit expression () and, correspondingly, tonic GABAergic currents () are up-regulated during the first postnatal week. Due to the depolarizing GABAergic responses during these stages (), these tonic GABAergic currents increase the excitability of the immature hippocampus (although GABAergic responses can mediate shunting inhibition even at depolarizing potentials; ). Accordingly, early network oscillations in the hippocampus, which depend on glutamatergic transmission and membrane properties of intrinsically bursting pyramidal neurons (; ; Sipila et al., 2006), are driven by a tonic GABAergic depolarization of these cells (Sipila et al., 2005). In the early postnatal hippocampus tonic GABAergic currents, mediated by α5 and γ2 subunit containing GABA receptors, enhance the excitability of pyramidal neurons, but not of interneurons (). Interestingly, in the adult hippocampus moderate tonic currents are more prominent in interneurons and can even promote excitation in these cells (Semyanov et al., 2003), although GABAA receptor activation mediate similar, slightly depolarizing actions in interneurons at both developmental stages (). Due to this slight depolarizing action, moderate tonic currents mediate an excitatory action in mature hippocampal interneurons, while shunting inhibition dominates at larger tonic conductances a (Song et al., 2011).
In the immature hippocampus a moderate increase in tonic GABAergic currents mediated by α5 containing receptors promote epileptiform discharges under low-Mg2+ condition, which are insufficient to induce epileptiform discharges in this preparation (; Figure 4). In the hippocampus of early postnatal rats a tonic activation of GABAB receptors does not control basal or stimulated GABA release (), although the GABAB specific agonist Baclofen reduces the amplitude of GABAergic postsynaptic currents, indicating the functional expression of GABAB receptors in this structure (). In contrast, it has been shown that a tonic activation of GABAB receptors decreases neurotransmitter release in GABAergic synapses in early postnatal hippocampus and neocortex (Safiulina and Cherubini, 2009; ). This observation indicates that ambient GABA can mediate a stringent feedback control via GABAB receptors during a developing stage when GABA can generate excitatory responses (; Valeeva et al., 2010). In addition, these presynaptic GABAB receptors may also limit the amount of ambient GABA originating from synaptic release. However, in summary these results demonstrate that a tonic activation of GABAA receptors can increase the excitability in early postnatal circuits.
FIGURE 4
ORIGIN AND NATURE OF ENDOGENOUS GABAergic AGONISTS
The important role of GABA for neuronal development was challenged by the observation that even a complete knockout of both GAD-65 and GAD-67 did not induce gross disturbances in the neocortex and hippocampus until P0, albeit a virtually absence of GABA in the brains of these animals (). Although this study may refute the importance of GABA as neurotrophic substance during prenatal development, it can also indicate that other factors can compensate the lack of GABA or even represent an additional important trophic neurotransmitter during early corticogenesis.
In this respect it is important to reconsider that most studies investigating tonic currents identify such current by the blockade of GABAA receptors and thus cannot provide any information about the nature of the endogenous ligand of extrasynaptic GABA receptors. One intriguing candidate for such a substance is taurine, which is an agonist of GABAA, GABAB, and glycine receptors (). In rat and human fetal brain taurine is the most abundant neurotransmitter (; ). In early postnatal cortex a glycinergic agonist, presumably taurine, is released upon electrical stimulation in a Ca2+ and action potential independent manner () and in the presence of a hypoosmolar solution (; ), indicating that taurine can be release in the immature central nervous system (CNS) mainly by non-synaptic processes. Possible release pathways are volume-sensitive organic osmolyte channels or a reversal of the taurine transporter (). Analysis of the chemoattractant diffusible factors released by the CP neurons also identified taurine as a possible candidate () and it has been shown by the same authors that taurine modulates radial migration via activation of GABAB receptors (). In accordance with these in vitro studies, migration deficits have been found in kittens born from taurine-deficient mothers (). Taurine may, however, act mainly as an agonist for glycine receptors, which have been found in the immature CNS (Wu et al., 1992; ; ; ); which are supposed to be mainly activated by non-synaptically released taurine () and which are also directly involved in early developmental events like migration ().
However, the exact concentrations of interstitial GABA and taurine are unknown, since most reports document only total neurotransmitter contents. Considering the lack of vGAT and synaptic release during early development and the high intracellular taurine concentration, the abundance of taurine in the interstitial space may be considerably higher than that of GABA. On the other hand, the amount of taurine released by CP neurons is similar to the GABA release (), indicating that at least in this niche GABA will by its substantially higher affinity to both GABAA and GABAB receptors mediate a more pronounced effect.
Overall, the observations summarized in this review indicate (i) that the molecular constituents of the GABAergic system are present at very early developmental stages before the onset of synaptogenesis, (ii) that tonic GABAergic currents are acting in the developing CNS, (iii) that GABA mediates a trophic action on neurogenesis, neuronal migration and differentiation in developmental niches which lack synaptic GABAergic signaling, and (iv) that tonic GABAergic currents regulate neuronal activity even after the establishment of reliable GABAergic synaptic transmission. In summary, all these studies provide compelling evidence for the important role of extrasynaptic GABAergic signaling during early neuronal development. Accordingly, it has been found that substances, which interfere with the GABAergic system during such early developmental stages, and thus affect mostly non-synaptic processes, disturb the proper development of the central nervous system. For example, antiepileptic drugs acting on GABA mechanisms lead to hippocampal and neocortical dysplasias, most probably by disturbing proliferation and radial migration (). Similarly, prenatal exposure to ethanol, which is supposed to act partially via an activation of δ subunit containing receptors (), leads to a decreased proliferation () and migration () of cortical neurons. These examples demonstrate that the important role of extrasynaptic GABAergic signaling during neuronal development has to be considered in therapeutical intervention during pregnancy. On the other hand, the early expression of different elements of the GABAergic system during very early stages of neuronal development emphasizes the close interaction between genetic programs and functional responses of neuronal progenitors or neuroblasts. To elucidate how genetic programs determine the electrical properties of the developing nervous system and how, vice versa, the tonic activation of neurotransmitter receptors influence the transcription of genes will be essential questions for the further comprehension of early neuronal development.
Statements
Acknowledgments
Supported by grants of the Deutsche Forschungsgemeinschaft to the authors.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Summary
Keywords
GABAA receptor, GABAB receptor, GABA transporter, GABA metabolism, neuronal proliferation, migration, taurine, review
Citation
Kilb W, Kirischuk S and Luhmann HJ (2013) Role of tonic GABAergic currents during pre- and early postnatal rodent development. Front. Neural Circuits 7:139. doi: 10.3389/fncir.2013.00139
Received
14 June 2013
Accepted
16 August 2013
Published
03 September 2013
Volume
7 - 2013
Edited by
Alexey Semyanov, RIKEN Brain Science Institute, Japan
Reviewed by
Yehezkel Ben-Ari, Institut National de la Santé et de la Recherche Médicale, France; Kai Kaila, University of Helsinki, Finland
Copyright
© Kilb, Kirischuk and Luhmann.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Sergei Kirischuk, Institute of Physiology and Pathophysiology, University Medical Center Mainz, Duesbergweg 6, D-55128 Mainz, Germany e-mail: kirischu@uni-mainz.de
This article was submitted to the journal Frontiers in Neural Circuits.
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