GABAergic Circuit Development and Its Implication for CNS Disorders

The function of the cerebral cortex requires the coordinated action of two major neuronal subtypes, the glutamatergic projection neurons and the GABAergic interneurons. Although , in terms of numbers, GABAergic interneurons represent a minor cell population compared to glutamater-gic neurons in the neocortex, they play an important role in modulating network dynamics of neocortical circuits. Indeed, GABAergic interneurons have been shown to control neuronal excitability and integration, and they have been implicated in the generation of temporal synchrony and oscillatory behavior among networks of pyramidal neu-rons. Such oscillations within and across neural systems are believed to serve various complex functions, such as perception, movement initiation, and memory. Recently, the development of GABAergic inhibition has been shown to be a key determinant for critical period plasticity of cortical circuits. Critical periods represent heightened epochs of brain plasticity, during which experience can produce permanent , large-scale changes in neuronal circuits. Experience-dependent refinement of neural circuits has been described in many regions within the CNS, suggesting it is a fundamental mechanism for normal vertebrate CNS development. By regulating the onset and closure of critical periods, GABAer-gic interneurons may influence how experience shapes brain wiring during early life and adolescence. Considering the multifaceted role played by GABAergic cells in the development, function, and plasticity of neural circuits, it is not surprising that alterations in the development of GABAergic circuits per se have been implicated in various neurodevelopmental and psychiatric disorders such as schizophrenia, autism, and epilepsy. However, how modification of GABAergic circuit development contributes to specific pathologies is largely unknown. Furthermore, GABA mimetic drugs, such as benzodiazepines and certain antiepileptic drugs, are widely used in clinical practice, but whether and to what extent these drugs cause deleterious effect on the developing brain is still not clear. A better comprehension of the mechanisms underlying the development and plasticity of GABAergic interneurons will likely indicate which cellular substrates might be affected in neurodevelop-mental disorders. At the same time, identifying the genetics variants implicated in these disorders may generate major new insights into the normal and pathological function of GABAergic circuits. Our understanding of GABAergic interneurons function is challenged by their startling heterogeneity; indeed, different subtypes of interneurons display distinct morphology, physiological properties, connectivity patterns, and biochemical constituents. Recent technical advances have significantly accelerated progress in this field. In particular,