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.

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.

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.