The neocortex is the most complex neural system in the mammalian brain and is responsible for mediating the highest forms of perceptual and cognitive function. Central to our current understanding of the physiology of higher cortical function is the concept of synaptic plasticity, or use-dependent modifications of synaptic efficiency. When such activity proceeds in a focused and coherent manner the process is associated with normal behavior, healthy cortical development, and normal learning and memory formation. When the process becomes deranged and goes unchecked, the result is neuropathology, leading to mental disorder and abnormal behavior. Understanding normal cortical function and dysfunction, which is the overall objective of the proposed studies, must begin at the level of the local neuronal circuit. While most studies of this issue have concentrated on excitatory mechanisms, my focus will be on the mechanisms which oppose and thereby regulate excitability, namely synaptic GABAergic inhibition. Major goals of the proposed experiments are to characterize inhibitory neural circuits and inhibitory neurons in the rat somatosensory cortex. Recent work postulates that inhibition in the neocortex is mediated by two populations of interneurons, one responsible for fast GABA-A, and the other, slow GABA-B inhibition. In vitro experiments will be carried out to test this hypothesis with regard to the following issues: 1) Specifying the functional relationship of inhibitory neurons to pyramidal neurons (i.e. spatial properties and unitary synaptic potentials), 2) Elucidating the physiology and morphology of inhibitory neurons, 3) Defining non-NMDA and NMDA ionotropic excitatory input onto inhibitory neurons, and 4) Defining GABAergic inhibitory input onto inhibitory neurons. Experiments will be preformed using standard intracellular or patch clamp recordings of layer V neurons and inhibitory interneurons in neocortical slices. Inhibitory neurons will be identified by their action on postsynaptic cells and will be marked by both extracellular and intracellular labelling techniques to allow correlation of physiology and morphology. The proposed experiments will provide information on cortical information processing, and suggest mechanisms for the pathogenesis of excitotoxicity.
