Early postnatal experience can profoundly influence the structure and function of the mammalian neocortex. The cellular and molecular mechanisms underlying the critical period plasticity in visual cortex will provide insight into the development of other sensory and cognitive functions, learning and memory, rehabilitation, and regeneration. It has been suggested that the development of GABAergic inhibitory mechanisms may initiate and drive the critical period for ocular dominance (OD) plasticity in visual cortex. GABAergic interneurons are morphologically and physiologically diverse and control cortical excitability at precise spatial and temporal domains. We hypothesize that the functional maturation of distinct classes of GABAergic circuits allows enhanced GABAergic synaptic transmission during the critical period and contributes to OD plasticity. We will use cell type-specific promoters and bacterial artificial chromosome transgenics in mice to label specific classes of GABAergic interneurons in living tissue. We will then characterize the functional maturation of such GFP labeled interneurons in cortical slices using electrophysiology and two-photon imaging. Furthermore, we will alter the expression of the GABA synthetic enzyme GAD65 in two classes of GABAergic circuits: the parvalbumin- containing basket interneurons and the somatostatin- containing bitufted interneurons. We will then examine the consequences of such cell type-specific manipulation of GABAergic transmission on the critical period of OD plasticity using single unit recording in visual cortex. Maturation of cortical GABAergic circuitry is in turn strongly influenced by visual experience. We hypothesize that the brain-derived neurotrophic factor (BDNF) is a key molecular signal that promotes the normal maturation of GABAergic interneurons and retards their development during visual deprivation. We will examine whether BDNF overexpression in visual cortex in transgenic mice can rescue the effects of dark rearing on the maturation of GABAergic circuits and on visual function using immunohistochemistry and electrophysiology. A genetic approach to the function and development of specific classes of GABAergic circuits will contribute to our understanding of the microarchitecture and information processing in normal neocortex and its deregulated states such as epilepsy.
