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The asynchronous GABA A EPSC s generated in the presence of Sr 2 are evoked quantal events. A, Representative traces of evoked GABA A EPSC s recorded in the presence of C a 2 (Ca 2-ACSF ) or Sr 2 (Sr 2-ACSF ) in the presence of C NQX (10 M) and D-AP5 (50 M). A 500 msec time window before and 200 msec after the stimulus artifact was used to measured, respectively, the background and poststimulus frequency and amplitude of the GABA A EPSC s. B, Times course change in the frequency (top graph) and amplitude (bottom graph) of GABA A EPSC s for the cell depicted in A. The variation in frequency is illustrated as the difference between the poststimulus frequency (F (B) ) and the background frequency (F (A) ). C, Cumulative histograms of the normalized amplitude distribution of the asynchronous GABA A EPSC s measured during the poststimulus 500 msec time window in C a 2-AC SF (E) and Sr 2-AC SF (F) (n 5). The insets show superimposed averaged (n 20) GABA A EPSC s for one experiment under each set of conditions. D, Cumulative histograms of the normalized amplitude distribution of the mGABA A EPSC s, measured after addition of TTX (1 M) and sucrose (50 mM) (E; n 5) and the asynchronous GABA A EPSC s measured during the poststimulus 500 msec time window in Sr 2-AC SF (F; n 5). The insets show superimposed averaged (n 20) quantal events for one experiment under each set of conditions.
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Synaptic plasticity at excitatory glutamatergic synapses is believed to be instrumental in the maturation of neuronal networks. Using whole-cell patch-clamp recordings, we have studied the mechanisms of induction and expression of long-term depression at excitatory GABAergic synapses in the neonatal rat hippocampus (LTD(GABA-A)). We report that the...
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... To quantif y the effect of TS on the amplitude of GABA A EPSC s, analysis was only performed on single isolated events within the same time window. Averaged cumulative histograms were obtained by normalizing each distribution to the corresponding median value ob- tained from the distribution of asynchronous GABA A EPSC s in Sr 2 - AC SF (see Fig. 4C-D), before tetanization (see Fig. 5C), or recorded at 80 mV (see Fig. 5E). In most experiments a control and a test pathway were monitored, and comparisons of the slope and amplitude of the test GABA A -mediated responses were performed with the control pathway. The amplitude of the TS-induced current was measured at the peak of the ...
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... first compared the back- ground and poststimulus frequency of GABA A EPSC s occurring during a 500 msec time window before and 200 msec after the stimulus artifact. An example of such an experiment is shown in Figure 4 A,B. In Ca 2 -AC SF, the poststimulus and back- ground frequencies of GABA A EPSC s were comparable (16.1 2.5 vs 18.1 0.9 Hz; p 0.31) (Fig. 4 B). ...
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... compared the back- ground and poststimulus frequency of GABA A EPSC s occurring during a 500 msec time window before and 200 msec after the stimulus artifact. An example of such an experiment is shown in Figure 4 A,B. In Ca 2 -AC SF, the poststimulus and back- ground frequencies of GABA A EPSC s were comparable (16.1 2.5 vs 18.1 0.9 Hz; p 0.31) (Fig. 4 B). In contrast, 5-10 min after perf usion with Sr 2 -AC SF, which led to a reduction of the evoked GABA A EPSC s amplitude (from 289 15 to 79 8pA; p 0.001) (Fig. 4 A), the poststimu- lus frequency of GABA A EPSC s significantly increased in comparison to the background frequency (13.6 1.6 vs 7.8 0.6 Hz; p 0.001) (Fig. 4 A,B). Therefore, ...
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... of such an experiment is shown in Figure 4 A,B. In Ca 2 -AC SF, the poststimulus and back- ground frequencies of GABA A EPSC s were comparable (16.1 2.5 vs 18.1 0.9 Hz; p 0.31) (Fig. 4 B). In contrast, 5-10 min after perf usion with Sr 2 -AC SF, which led to a reduction of the evoked GABA A EPSC s amplitude (from 289 15 to 79 8pA; p 0.001) (Fig. 4 A), the poststimu- lus frequency of GABA A EPSC s significantly increased in comparison to the background frequency (13.6 1.6 vs 7.8 0.6 Hz; p 0.001) (Fig. 4 A,B). Therefore, most events de- tected after the stimulation were indeed evoked asynchronous GABA A EPSC ...
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... vs 18.1 0.9 Hz; p 0.31) (Fig. 4 B). In contrast, 5-10 min after perf usion with Sr 2 -AC SF, which led to a reduction of the evoked GABA A EPSC s amplitude (from 289 15 to 79 8pA; p 0.001) (Fig. 4 A), the poststimu- lus frequency of GABA A EPSC s significantly increased in comparison to the background frequency (13.6 1.6 vs 7.8 0.6 Hz; p 0.001) (Fig. 4 A,B). Therefore, most events de- tected after the stimulation were indeed evoked asynchronous GABA A EPSC ...
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... also observed a significant and stable decrease in the amplitude of the GABA A EPSCs occurring during the poststimu- lus analysis. For the cell depicted in Figure 4 A,B, the mean amplitude of GABA A EPSCs decreased from 29 2 pA in Ca 2 -ACSF to 15 1 pA ( p 0.001) 10 min after perfusion with Sr 2 -ACSF and remained constant at 14 1 pA ( p 0.35) 10 min later. The reduction in the amplitude of GABA A EPSCs was further demonstrated by the shift to the left of the normalized cumulative amplitude distribution (Fig. 4C) (n 4; p 0.005). ...
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... 4 A,B, the mean amplitude of GABA A EPSCs decreased from 29 2 pA in Ca 2 -ACSF to 15 1 pA ( p 0.001) 10 min after perfusion with Sr 2 -ACSF and remained constant at 14 1 pA ( p 0.35) 10 min later. The reduction in the amplitude of GABA A EPSCs was further demonstrated by the shift to the left of the normalized cumulative amplitude distribution (Fig. 4C) (n 4; p 0.005). We then compared the amplitude of the evoked asynchronous GABA A EPSCs that occurred during the same 500 msec time window after the stimulation with the amplitude of spontaneous TTX-insensitive miniature GABA A EPSCs re- corded in hypertonic Sr 2 -ACSF (mGABA A EPSCs). The am- plitude distributions of evoked asynchronous ...
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... of the evoked asynchronous GABA A EPSCs that occurred during the same 500 msec time window after the stimulation with the amplitude of spontaneous TTX-insensitive miniature GABA A EPSCs re- corded in hypertonic Sr 2 -ACSF (mGABA A EPSCs). The am- plitude distributions of evoked asynchronous GABA A EPSCs were similar to those of mGABA A EPSCs (Fig. 4 D) ( p 0.28; n 5), indicating that they were quantal ...
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... distributions obtained before and 20 min after TS (Fig. 5C) (p 0.61; n 6); the average amplitude of evoked asynchronous GABA A EPSC s after TS was 94.2 6.1% of the pretetanized values (Fig. 5D) ( p 0.36; n 6). In control experiments, long-term recordings (up to 1 hr) in Sr 2 -ACSF altered neither the frequency (Fig. 5B) (n 8) nor the amplitude (Fig. 4 B) of the evoked asynchronous GABA A EPSCs if TS was not delivered. These data therefore show that the decrease in the frequency observed after TS is not caused by a rundown of GABA A receptor-mediated ...
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Citations
... However, a striking difference during the first postnatal week is how SPON and LSO neurons respond to GABA and glycine. Because of their high intracellular chloride concentration, LSO neurons respond to MNTB stimulation with membrane depolarization, an increase in the intracellular calcium concentration, and triggering action potentials (Kandler and Friauf, 1995;Ehrlich et al., 1999;Kakazu et al., 1999;Kullmann and Kandler, 2001;Kullmann et al., 2002;Lee et al., 2016), which is often linked to activity-dependent synaptic plasticity (Caillard et al., 1999;Deidda et al., 2015;Brady et al., 2018). This is in stark contrast to SPON neurons, in which GABA and glycine elicit hyperpolarizing responses already at birth because of the early expression of functional KCC2 transporters (Löhrke et al., 2005;Kopp-Scheinpflug et al., 2011). ...
The medial nucleus of the trapezoid body (MNTB) in the auditory brainstem is the principal source of synaptic inhibition to several functionally distinct auditory nuclei. Prominent projections of individual MNTB neurons comprise the major binaural nuclei that are involved in the early processing stages of sound localization as well as the superior paraolivary nucleus (SPON), which contains monaural neurons that extract rapid changes in sound intensity to detect sound gaps and rhythmic oscillations that commonly occur in animal calls and human speech. While the processes that guide the development and refinement of MNTB axon collaterals to the binaural nuclei have become increasingly understood, little is known about the development of MNTB collaterals to the monaural SPON. In this study, we investigated the development of MNTB-SPON connections in mice of both sexes from shortly after birth to three weeks of age, which encompasses the time before and after hearing onset. Individual axon reconstructions and electrophysiological analysis of MNTB-SPON connectivity demonstrate a dramatic increase in the number of MNTB axonal boutons in the SPON before hearing onset. However, this proliferation was not accompanied by changes in the strength of MNTB-SPON connections or by changes in the structural or functional topographic precision. However, following hearing onset, the spread of single-axon boutons along the tonotopic axis increased, indicating an unexpected decrease in the tonotopic precision of the MNTB-SPON pathway. These results provide new insight into the development and organization of inhibition to SPON neurons and the regulation of developmental plasticity in diverging inhibitory pathways.
Significance Statement
The superior paraolivary nucleus (SPON) is a prominent auditory brainstem nucleus involved in the early detection of sound gaps and rhythmic oscillations. The ability of SPON neurons to fire at the offset of sound depends on strong and precise synaptic inhibition provided by glycinergic neurons in the medial nucleus of the trapezoid body (MNTB). Here, we investigated the anatomical and physiological maturation of MNTB-LSO connectivity in mice before and after the onset of hearing. We observed a period of bouton proliferation without accompanying changes in topographic precision before hearing onset. This was followed by bouton elimination and an unexpected decrease in the tonotopic precision after hearing onset. These results provide new insight into the development of inhibition to the SPON.
... While it is not entirely clear what role GABA A Rs are playing to support induction of this LTCC-dependent LTP in WT neurons, one possibility is that by pairing HFS with depolarization to 0 mV we are allowing feed-forward inhibition onto CA1 neurons to instead produce outward, depolarizing excitatory Cl-currents through synaptic GABA A Rs to assist in driving LTCC opening and Ca 2+ influx that then activates signaling pathways required for AMPAR potentiation. Indeed, during early postnatal development GABA is excitatory due to high [Cl − ] internal , and the excitatory actions of GABA A R activation promote LTCC opening that controls the development and strengthening of both inhibitory and excitatory synapses to establish E/I balance in the hippocampus and other brain regions (Ben-Ari, 2002, 2014Ben-Ari et al., 2007;Caillard et al., 1999;McLean et al., 1996;Oh and Smith, 2019;Sanderson et al., 2012;Zucca and Valenzuela, 2010). Thus, the reduced GABAergic synaptic transmission in TS2-neo CA1 neurons may be insufficient to drive enough LTCC opening to induce this form of HFS-LTP, despite the channel gain-offunction conferred by the G406R mutation. ...
Genetic alterations in autism spectrum disorders (ASD) frequently disrupt balance between synaptic excitation and inhibition and alter plasticity in the hippocampal CA1 region. Individuals with Timothy Syndrome (TS), a genetic disorder caused by CaV1.2 L-type Ca²⁺ channel (LTCC) gain-of function mutations, such as G406R, exhibit social deficits, repetitive behaviors, and cognitive impairments characteristic of ASD that are phenocopied in TS2-neo mice expressing G406R. Here, we characterized hippocampal CA1 synaptic function in male TS2-neo mice and found basal excitatory transmission was slightly increased and inhibitory transmission strongly decreased. We also found distinct impacts on two LTCC-dependent forms of long-term potentiation (LTP) synaptic plasticity that were not readily consistent with LTCC gain-of-function. LTP induced by high-frequency stimulation (HFS) was strongly impaired in TS2-neo mice, suggesting decreased LTCC function. Yet, CaV1.2 expression, basal phosphorylation, and current density were similar for WT and TS2-neo. However, this HFS-LTP also required GABAA receptor activity, and thus may be impaired in TS2-neo due to decreased inhibitory transmission. In contrast, LTP induced in WT mice by prolonged theta-train (PTT) stimulation in the presence of a β-adrenergic receptor agonist to increase CaV1.2 phosphorylation was partially induced in TS2-neo mice by PTT stimulation alone, consistent with increased LTCC function. Overall, our findings provide insights regarding how altered CaV1.2 channel function disrupts basal transmission and plasticity that could be relevant for neurobehavioral alterations in ASD.
This article is part of the Special Issue on ‘L-type calcium channel mechanisms in neuropsychiatric disorders’.
... How injury-induced KCC2 downregulation contributes to synaptic stripping can be linked to its facilitating of a depolarizing shift in GABA-evoked responses. In cultured immature hippocampal neurons, depolarizing GABAergic signaling is associated with long-term depression of both GABAergic [50], and glutamatergic synapses [51], whilst precocious KCC2 overexpression facilitates a relative increase in GABAergic but not glutamatergic synapses [52]. Notably, CaMKII-KCC2 mice still show signi cant VGLUT1 synaptic stripping at 42-days post-SNC (Fig. 7A), which would appear to partially contradict this idea. ...
Injury to mature neurons induces downregulated KCC2 expression and activity, resulting in elevated intracellular [Cl ⁻ ] and depolarized GABAergic signaling. This phenotype mirrors immature neurons wherein GABA-evoked depolarizations facilitate neuronal circuit maturation. Thus, injury-induced KCC2 downregulation is broadly speculated to similarly facilitate neuronal circuit repair. We test this hypothesis in spinal cord motoneurons injured by sciatic nerve crush, using transgenic (CaMKII-KCC2) mice wherein conditional CaMKIIα promoter-KCC2 expression coupling selectively prevents injury-induced KCC2 downregulation. We demonstrate, via an accelerating rotarod assay, impaired motor function recovery in CaMKII-KCC2 mice relative to wild-type mice. Across both cohorts, we observe similar motoneuron survival and re-innervation rates, but differing post-injury reorganization patterns of synaptic input to motoneuron somas – for wild-type, both VGLUT1-positive (excitatory) and GAD67-positive (inhibitory) terminal counts decrease; for CaMKII-KCC2, only VGLUT1-positive terminal counts decrease. Finally, we recapitulate the impaired motor function recovery of CaMKII-KCC2 mice in wild-type mice via local spinal cord injections of bicuculline (GABA A receptor blockade) or bumetanide (lowers intracellular [Cl ⁻ ] by NKCC1 blockade) during the early post-injury period. Thus, our results provide direct evidence that injury-induced KCC2 downregulation enhances motor function recovery and suggest an underlying mechanism of depolarizing GABAergic signaling driving adaptive neuronal circuit reconfiguration that preserves appropriate excitation-inhibition balance.
... Calmodulin binding is another function highlighted by the GO analysis. Calmodulin controls Ca 2+ signaling and regulates the propagation of nerve impulse; probably, it is also involved in ethanol neurotoxicity (Caillard et al., 1999). Furthermore, IPA indicated the network "Embryonic Development, Organism Development, Cellular Development". ...
Ethanol exposure during gestation is an early life stressor that profoundly dysregulates structure and function s of the embryonal nervous system, altering the cognitive and
behavioral development. Such dysregulation is also achieved by epigenetic mechanisms, which, altering the chromatin structure , redraw the entire pattern of gene
expression . In parallel, an oxidative stress response at the cellular level and a global
upregulation of neuroendocrine stress response, regulated by the HPA axis, exist and
persist in adulthood. This neurobehavioral framework matches those observed in other
psychiatric diseases such as mood diseases, depression, autism; those early life
stressing events, although probably triggered by specific and different epigenetic
mechanisms, give rise to largely overlapping neurobehavioral phenotypes. An early
diagnosis of prenatal alcohol exposure, using reliable markers of ethanol intake,
together with a deeper understanding of the pathogenic mechanisms, some of them
reversible by their nature, can offer a temporal “window” of intervention. Supplementing
mother’s diet with protective and antioxidant substances in addition to supportive
psychological therapies can protect newborns from being affected.
... In previous studies we have shown that these parameters can be used in the developing rat hippocampus to assess the site of expression of a depression in eGABAA-PSC amplitude (Caillard et al., 1998(Caillard et al., , 1999Tosetti et al., 2005). Overall, these data indicate that leptin-induced LLP-GABAA does not arise from a uniform postsynaptic change in the number or properties of GABAARs, but rather from an increase in the number of functional GABAergic synapses. ...
... We also found that leptin enhances the frequency of mGABAA-PSCs and decreases the CV of eGABAA-PSCs, consistent with a presynaptic alteration in GABA release and/or a modification in the number of functional GABAergic synapses recruited. However, whereas manipulating presynaptic GABA release alters the PPR of eGABAA-PSCs (Caillard et al., 1999), we observed no modification in the PPR of eGABAA-PSCs following leptin application. Taken together, these results argue that the leptininduced LLP-GABAA is expressed as an increase in the number of functional GABAergic synapses. ...
The present dissertation tackles the larger question of how external cues impact the development of the central nervous system. Our specific aim was to explore the effect of leptin, an adipocyte-derived hormone, on GABAergic plasticity in the developing rodent hippocampus. We used acute hippocampal slices of newborn rats to show that leptin induces a long lasting potentiation of the frequency of miniature GABAergic activity. Using pharmacological tools we found that this event requires a postsynaptic increase in intracellular calcium as well as specific postsynaptic signaling pathways. To address the mechanistic action of leptin we confirmed the leptin-induced plasticity on hippocampal cultures and began to develop a method to measure the morphological correlate of GABAergic synapses in culture. Applying this method suggested that the leptin-induced GABAergic plasticity might occur with a constant density of postsynaptic GABAA receptor puncta. Taken together, these data show that leptin induces a potentiation of GABAergic activity in developing hippocampal neurons, perhaps by recruiting clusters of GABAA receptors expressed at the membrane to form newly functional GABAergic synapses. In addition we found that CA3 pyramidal neurons of leptin-deficient ob/ob mice exhibit lower miniature GABAergic activity compared to wild type littermates, which suggests that leptin contributes to the development of the hippocampal GABAergic circuitry in vivo. Overall, these studies shed a new light on the development of admittedly "higher-level" cerebral regions which were found here to integrate "lower-level", peripheral signals to shape their development.
... In previous studies we have shown that these parameters can be used in the developing rat hippocampus to assess the site of expression of a depression in eGABA A -PSC amplitude (Caillard et al., 1998(Caillard et al., , 1999Tosetti et al., 2005). Here we further validated this approach in the case of a potentiation of eGABA A -PSC amplitude, through manipulations with a controlled site of expression: 1 • a postsynaptic increase in GABA driving force ( Figure 5E point-up triangle), by hyperpolarizing the recorded neuron, increased eGABA A -PSC amplitude (123 ± 15 pA to 193 ± 14 pA, n = 4, p = 0.01) with no change in PPR (Caillard et al., 1998) nor CV (0.43 ± 0.04 to 0.39 ± 0.01, p = 0.4); 2 • a presynaptic increase of GABA release (Figure 5E point-down triangle), by increasing the extracellular Ca 2+ /Mg 2+ ratio, increased eGABA A -PSC amplitude (184 ± 32 pA to 297 ± 46 pA, n = 3), increased the PPR (Caillard et al., 1998) and decreased the CV (0.42 ± 0.02 to 0.24 ± 0.02); and 3 • an increase in the number of recruited synapses (Figure 5E open diamond), by increasing the stimulus intensity, increased eGABA A -PSC amplitude (96 ± 16 pA to 233 ± 13 pA, n = 5, p = 0.02) with no change in PPR (0.75 ± 0.09 to 0.90 ± 0.05, p = 0.15) and decreased the CV (0.53 ± 0.07 to 0.27 ± 0.03, p = 0.008). ...
... We also found that leptin enhances the frequency of mGABA A -PSCs and decreases the CV of eGABA A -PSCs, consistent with a presynaptic alteration in GABA release and/or a modification in the number of functional GABAergic synapses recruited. However, whereas manipulating presynaptic GABA release alters the PPR of eGABA A -PSCs (Caillard et al., 1999), we observed no modification in the PPR of eGABA A -PSCs following leptin application. Taken together, these results argue that the leptin-induced LLP-GABA A is expressed as an increase in the number of functional GABAergic synapses. ...
It is becoming increasingly clear that leptin is not only a hormone regulating energy homeostasis but also a neurotrophic factor impacting a number of brain regions, including the hippocampus. Although leptin promotes the development of GABAergic transmission in the hypothalamus, little is known about its action on the GABAergic system in the hippocampus. Here we show that leptin modulates GABAergic transmission onto developing CA3 pyramidal cells of newborn rats. Specifically, leptin induces a long-lasting potentiation (LLP-GABAA) of miniature GABAA receptor-mediated postsynaptic current (GABAA-PSC) frequency. Leptin also increases the amplitude of evoked GABAA-PSCs in a subset of neurons along with a decrease in the coefficient of variation and no change in the paired-pulse ratio, pointing to an increased recruitment of functional synapses. Adding pharmacological blockers to the recording pipette showed that the leptin-induced LLP-GABAA requires postsynaptic calcium released from internal stores, as well as postsynaptic MAPK/ERK kinases 1 and/or 2 (MEK1/2), phosphoinositide 3 kinase (PI3K) and calcium-calmodulin kinase kinase (CaMKK). Finally, study of CA3 pyramidal cells in leptin-deficient ob/ob mice revealed a reduction in the basal frequency of miniature GABAA-PSCs compared to wild type littermates. In addition, presynaptic GAD65 immunostaining was reduced in the CA3 stratum pyramidale of mutant animals, both results converging to suggest a decreased number of functional GABAergic synapses in ob/ob mice. Overall, these results show that leptin potentiates and promotes the development of GABAergic synaptic transmission in the developing hippocampus likely via an increase in the number of functional synapses, and provide insights into the intracellular pathways mediating this effect. This study further extends the scope of leptin's neurotrophic action to a key regulator of hippocampal development and function, namely GABAergic transmission.
... The induction of this phenomenon has been attributed to GABA A receptormediated depolarization, leading to NMDA receptor-mediated Ca 2+ influx. Interestingly, the same conditioning stimuli resulted in LTP when NMDA receptors were blocked (Caillard et al., 1999), suggesting that different forms of plasticity can coexist. A possible mediator for LTP induction is BDNF, which can be released in an activity-dependent manner from dendrites (Kuczewski et al., 2008) and plays a role in strengthening GABAergic synapses early in development (Gubellini et al., 2005; Inagaki et al., 2008; Sivakumaran et al., 2009; Peng et al., 2010). ...
... During development, strengthening of GABAergic synapses in response to postsynaptic activity (McLean et al., 1996; Caillard et al., 1999; Xu et al., 2008) may represent a tuning of inhibition to counteract overexcitation of target neurons. In keeping with this expectation, experimental suppression of activity in neuronal culture results in loss of GABA A receptors (Kilman et al., 2002). ...
Until recently, the study of plasticity of neural circuits focused almost exclusively on potentiation and depression at excitatory synapses on principal cells. Other elements in the neural circuitry, such as inhibitory synapses on principal cells and the synapses recruiting interneurons, were assumed to be relatively inflexible, as befits a role of inhibition in maintaining stable levels and accurate timing of neuronal activity. It is now evident that inhibition is highly plastic, with multiple underlying cellular mechanisms. This Review considers these recent developments, focusing mainly on functional and structural changes in GABAergic inhibition of principal cells and long-term plasticity of glutamateric recruitment of inhibitory interneurons in the mammalian forebrain. A major challenge is to identify the adaptive roles of these different forms of plasticity, taking into account the roles of inhibition in the regulation of excitability, generation of population oscillations, and precise timing of neuronal firing.
... This has been confirmed in a wide range of animal species from worms to higher mammals , brain structures and preparations from neuronal cultures to slices, intact organs in vitro and in vivo [see the large table with the papers showing the developmental sequence in Ben-Ari et al Physiological reviews (Ben-Ari et al., 2007)]. The activation of GABA A and glycine receptors during early postnatal development routinely produces membrane depolarization, which, in some occasion, reach spike threshold to generate sodium action potentials (Chen et al., 1996; Khazipov et al., 1997; Leinekugel et al., 1997; Mienville, 1998; Dzhala and Staley, 2003), the activation of the non-inactivating sodium currents (Valeeva et al., 2010), the activation of voltage gated calcium currents (Leinekugel et al., 1997) and the removal of the voltage dependent Mg ++ block of NMDA channels also leading to large calcium influx (McLean et al., 1996; Leinekugel et al., 1997; Caillard et al., 1999). The GABA/NMDA links (Ben-Ari et al., 1997) has been reinforced recently with immuno-cytochemical observations (Cserep et al., 2012). ...
DURING BRAIN DEVELOPMENT, THERE IS A PROGRESSIVE REDUCTION OF INTRACELLULAR CHLORIDE ASSOCIATED WITH A SHIFT IN GABA POLARITY: GABA depolarizes and occasionally excites immature neurons, subsequently hyperpolarizing them at later stages of development. This sequence, which has been observed in a wide range of animal species, brain structures and preparations, is thought to play an important role in activity-dependent formation and modulation of functional circuits. This sequence has also been considerably reinforced recently with new data pointing to an evolutionary preserved rule. In a recent "Hypothesis and Theory Article," the excitatory action of GABA in early brain development is suggested to be "an experimental artefact" (Bregestovski and Bernard, 2012). The authors suggest that the excitatory action of GABA is due to an inadequate/insufficient energy supply in glucose-perfused slices and/or to the damage produced by the slicing procedure. However, these observations have been repeatedly contradicted by many groups and are inconsistent with a large body of evidence including the fact that the developmental shift is neither restricted to slices nor to rodents. We summarize the overwhelming evidence in support of both excitatory GABA during development, and the implications this has in developmental neurobiology.
... GABAergic neurosteroids were recently shown to mediate the effects of EtOH on LTP (Izumi et al., 2007). During the third-trimester equivalent, GABA A receptors will likely have a dual excitatory and inhibitory action and may actually facilitate LTP induction under some conditions (Caillard et al., 1999). In addition, the inhibitory actions of EtOH on LTP were occluded by an angiotensin 1 receptor blocker, and this receptor may also be involved in the mechanism by which EtOH affects LTP during the neonatal period of rat development (Wayner et al., 1993). ...
... [92] Developing Auditory Cortex BDNF-TrkB signaling Postsynaptic? [41] I-LTD Hippocampus (CA1) eCB signaling, presynaptic activity, Rim1α Presynaptic [9,15*,93] Lateral Amygdala eCB signaling, postsynaptic PKA, Rim1α Presynaptic [10,11,93] Prefrontal cortex (L2/3, L5) eCB signaling, D2R activation Presynaptic [16] Developing Visual Cortex (L2/3) eCB signaling Presynaptic [14*] Dorsal striatum eCB signaling Presynaptic [12] Superior colliculus eCB signaling Presynaptic [13] Neonatal Hippocampus (CA1 area) NMDAR-dependent, postsynaptic calcium Presynaptic [90,94] Hippocampus (CA1) NMDAR-dependent, calcineurin Postsynaptic [62] Deep Cerebellar Nuclei Postsynaptic calcium, protein phosphatses Postsynaptic [65] Developing Xenopus retinotectal system Activation of presynaptic NMDAR, relatively weak excitatory inputs Presynaptic [24,49] Ventral Tegmental Area eCB signaling, D2R activation Pre and postsynaptic [17,19] Developing auditory brainstem Low frequency stimulation, postsynaptic calcium Postsynaptic [95] Bi-Directional plasticity Deep Cerebellar Nuclei Postsynaptic rebound firing determines polarity of plasticity ...
Experience-dependent modifications of neural circuits and function are believed to heavily depend on changes in synaptic efficacy such as LTP/LTD. Hence, much effort has been devoted to elucidating the mechanisms underlying these forms of synaptic plasticity. Although most of this work has focused on excitatory synapses, it is now clear that diverse mechanisms of long-term inhibitory plasticity have evolved to provide additional flexibility to neural circuits. By changing the excitatory/inhibitory balance, GABAergic plasticity can regulate excitability, neural circuit function and ultimately, contribute to learning and memory, and neural circuit refinement. Here we discuss recent advancements in our understanding of the mechanisms and functional relevance of GABAergic inhibitory synaptic plasticity.
