From early embryonic development to adulthood, GABA release participates in the construction of the mammalian cerebral cortex. The maturation of GABAergic neurotransmission is a protracted process which takes place in discrete steps and results from the dynamic interaction between developmentally directed gene expression and brain activity. During the course of development, GABAergic interneurons contribute to key aspects of the functional maturation of the cortex in different ways, from exerting a trophic role to pacing immature neural networks. In this review, we provide an overview of the maturation of GABAergic neurotransmission and discuss the role of GABAergic interneurons in cortical wiring, plasticity, and network activity during pre- and postnatal development. We also discuss psychiatric diseases that may be considered at least in part developmental disorders of the GABAergic system.

The subventricular zone (SVZ) of the lateral ventricles is the largest neurogenic niche of the postnatal brain. New SVZ-generated neurons migrate via the rostral migratory stream to the olfactory bulb (OB) where they functionally integrate into preexisting neuronal circuits. Nonsynaptic GABA signaling was previously shown to inhibit SVZ-derived neurogenesis. Here we identify the endogenous protein diazepam binding inhibitor (DBI) as a positive modulator of SVZ postnatal neurogenesis by regulating GABA activity in transit-amplifying cells. We performed DBI loss- and gain-of-function experiments in vivo at the peak of postnatal OB neuron generation in mice and demonstrate that DBI enhances proliferation by preventing SVZ progenitors to exit the cell cycle. Furthermore, we provide evidence that DBI exerts its effect on SVZ progenitors via its octadecaneuropeptide proteolytic product (ODN) by inhibiting GABA-induced currents. Together our data reveal a regulatory mechanism by which DBI counteracts the inhibitory effect of nonsynaptic GABA signaling on subventricular neuronal proliferation.

Neurodevelopmental disorders are multi-faceted and can lead to intellectual disability, autism spectrum disorder and language impairment. Mutations in the Forkhead box FOXP1 gene have been linked to all these disorders, suggesting that it may play a central role in various cognitive and social processes. To understand the role of Foxp1 in the context of neurodevelopment leading to alterations in cognition and behaviour, we generated mice with a brain-specific Foxp1 deletion (Nestin-CreFoxp1−/−mice). The mutant mice were viable and allowed for the first time the analysis of pre- and postnatal neurodevelopmental phenotypes, which included a pronounced disruption of the developing striatum and more subtle alterations in the hippocampus. More detailed analysis in the CA1 region revealed abnormal neuronal morphogenesis that was associated with reduced excitability and an imbalance of excitatory to inhibitory input in CA1 hippocampal neurons in Nestin-CreFoxp1−/− mice. Foxp1 ablation was also associated with various cognitive and social deficits, providing new insights into its behavioural importance.

In the hippocampus at birth, most glutamatergic synapses are immature and functionally ''silent'' either because the neurotransmitter is released in insufficient amount to activate low-affinity ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors or because the appropriate receptor system is missing or nonfunctional. Here we show that, in the newborn rat, a brief application of nicotine at immature Schaffer collateral-CA1 connections strongly enhances neurotransmitter release and converts presynaptically silent synapses into conductive ones. This effect is persistent and can be mimicked by endogenous acetylcholine released from cholinergic fibers. Thus, during a critical period of postnatal development, activation of nicotinic acetylcholine receptors contributes to the maturation of functional synaptic contacts and the wiring of adult hippocampal circuitry.excitatory postsynaptic currents ͉ cholinergic stimulation ͉ Schaffer collateral-CA1 synapses ͉ presynaptic effect ͉ increased probability of glutamate release

Exposure to stress during early life (infancy/childhood) has long-term effects on the structure and function of the prefrontal cortex (PFC), and increases the risk for adult depression and anxiety disorders. However, little is known about the molecular and cellular mechanisms of these effects. Here, we focused on changes induced by chronic maternal separation during the first 2 weeks of postnatal life. Unbiased mRNA expression profiling in the medial PFC (mPFC) of maternally separated (MS) pups identified an increased expression of myelin-related genes and a decreased expression of immediate early genes. Oligodendrocyte lineage markers and birthdating experiments indicated a precocious oligodendrocyte differentiation in the mPFC at P15, leading to a depletion of the oligodendrocyte progenitor pool in MS adults. We tested the role of neuronal activity in oligodendrogenesis, using designed receptors exclusively activated by designed drugs (DREADDs) techniques. hM4Di or hM3Dq constructs were transfected into mPFC neurons using fast-acting AAV8 viruses. Reduction of mPFC neuron excitability during the first 2 postnatal weeks caused a premature differentiation of oligodendrocytes similar to the MS pups, while chemogenetic activation normalised it in the MS animals. Bidirectional manipulation of neuron excitability in the mPFC during the P2-P14 period had long lasting effects on adult emotional behaviours and on temporal object recognition: hM4Di mimicked MS effects, while hM3Dq prevented the pro-depressive effects and short-term memory impairment of MS. Thus, our results identify neuronal activity as a critical target of early-life stress and demonstrate its function in controlling both postnatal oligodendrogenesis and adult mPFC-related behaviours.

Neurons continue to be generated in the subventricular zone (SVZ) throughout postnatal development and adulthood in rodents. Whereas in adults, virtually all neuroblasts migrate tangentially to the olfactory bulb via the rostral migratory stream (RMS), in neonates, a substantial fraction migrate radially through the corpus callosum (CC) to the cortex. Mechanisms of radial cortical migration have remained unknown. We investigated this by taking recourse to enhanced green fluorescent protein (EGFP)-labeled neuroblasts in the CC and deep cortical layers of neonatal mice and found that they are frequently located adjacent to vasculature. Using time-lapse 2-photon microscopy in acute brain slices, we demonstrate that EGFP-labeled neuroblasts migrate along blood vessels. Although in close proximity to blood vessels, migrating neuroblasts are separated from endothelial cells by 1-2 layers of astrocytic processes, as revealed by electron microscopal studies of retrovirally labeled postnatally born cells. We propose that 2 factors could contribute to the decline of radial migration to the cortex during postnatal development, namely the establishment of a glial sheath delineating the RMS and a gradual decrease in the density of blood vessels in the CC. Together, our data provide evidence for a new mode of radial cortical migration of SVZ-generated neurons involving vasculature and astrocytes.

GABAergic interneurons of the mouse cortex are generated embryonically in the ventral telencephalon. Recent evidence, however, indicated that a subset of cortical cells expressing interneuronal markers originate in the neonatal subventricular zone. This has raised interest in the functional development and incorporation of these postnatally generated cells into cortical circuits. Here we demonstrate that these cells integrate in the cortex, and that they constitute two distinct GABAergic interneuronal classes. Whereas one class reflects the tail end of embryonic interneuron genesis, the other class comprises interneurons that are exclusively generated perinatally and postnatally. The latter constitute a novel subclass of interneurons. They are preferentially located in the deeper layers of the olfactory and orbital cortices, exhibit a unique firing pattern and slow functional maturation. Based on their distinct morphology we termed them "small axonless neurons" and indeed, unlike other cortical neurons, they communicate with their neuronal partners via dendrodendritic synapses. Finally, we provide evidence that the number of small axonless neurons is enhanced by odor enrichment, a further indication that they integrate into neural circuits and participate to olfactory processing.

The hippocampus, a key structure in learning and memory processes, receives a powerful cholinergic innervation from the septum and contains nicotinic acetylcholine receptors (nAChRs). Early in postnatal development, activation of nAChRs by nicotine or endogenous acetylcholine contributes to enhance synaptic signalling. Here, the patch-clamp technique was used to assess the contribution of α7 and β2-containing (α7 * and β2 * ) nAChRs to nicotine-elicited modulation of GABAergic and glutamatergic activity at the network and single-cell level in the immature hippocampus of wild-type (WT), α7−/− and β2−/− mice. We found that α7 * and β2 * nAChRs were sufficient to modulate nicotine-induced increase in frequency of spontaneously occurring giant depolarizing potentials (GDPs), which are generated at the network level by the synergistic action of glutamate and depolarizing GABA, and thought to play a crucial role in neuronal wiring. However, α7 * but not β2 * receptors were essential in nicotine-induced increase of interictal discharge frequency recorded after postnatal day 3 in the presence of bicuculline, when GABA shifted from the depolarizing to the hyperpolarizing direction. To correlate these observations with nicotine-elicited changes in synaptic transmission, we recorded spontaneous GABAergic and glutamatergic postsynaptic currents in pyramidal cells and interneurons localized in stratum oriens, stratum pyramidale and stratum radiatum, in slices obtained from WT and knock-out animals. We found that early in postnatal life α7 * and β2 * nAChRs exert a fine regional modulation of GABAergic and glutamatergic transmission that underlies nicotine-elicited changes in network synchronization.