The Functional Maturation of Inhibitory Interneurons

DESCRIPTION (provided by applicant): GABAergic inhibitory interneurons in neocortex are a diverse group of cells that provide precise spatial and temporal control over the activity of local neural circuits. The importance of inhibitory interneurons has been demonstrated by studies of cortical plasticity and development, and by the observation of inhibitory defects in psychiatric disorders. The heterogeneity of these cells has previously made them difficult to study, however recent advances are beginning to allow for a more careful investigation of these cells and the circuits they form. We will use modern genetic and electrophysiological techniques to study the development of specific classes of cortical inhibitory interneurons during the critical period for ocular dominance (OD) plasticity, a canonical model of cortical plasticity. We will focus on two non-overlapping classes of cortical interneurons: Parvalbumin expressing cells, which have a fast-spiking phenotype and provide proximal inhibition to or near to the cell body, and somatostatin expressing cells, which have a regular-spiking phenotype and provide distal inhibition to the dendrites. The activity-dependence of inhibitory circuit formation will be studied by manipulating the two glutamic acid decarboxylase enzymes, the 65 and 67 kilodalton isoforms (GAD65 and GAD67, respectively), that synthesize the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Both of these enzymes have been shown to affect cortical development. Knockout of GAD65 prevents the occurrence of OD plasticity, whereas GAD67 regulates the morphological maturation of inhibitory synapses. In particular, GAD67 deficiency has been repeatedly demonstrated in schizophrenia. We will investigate the role of these enzymes in the functional maturation of specific classes of inhibitory interneurons. The knowledge gained from this study will help develop an understanding of how inhibition affects cortical plasticity and learning, and how dysfunction of the inhibitory system can contribute to a pathological state. Inhibitory interneurons are a diverse class of brain cells that regulate activity in local brain regions. Although previous studies have shown these cells to be important for learning and development, and to be dysfunctional in certain brain disorders, such as schizophrenia and autism, the complexity of these cells has made it difficult to study them. We are using modern genetic tools that now allow us to study these cells in a dependable and precise manner, which should lead to a better understanding of the role these cells play in healthy brain development, and how their dysfunction can contribute to a disease state.