Several disorders in mental function have been correlated with cellular aberrations in the cerebral cortex. The nature of these aberrations indicates that they arise early in development during the genesis and migration of neurons. All neurons within the cerebral cortex are generated within a proscribed region, the ventricular zone (VZ), throughout a discrete and defined period. It is becoming increasingly clear that signals acting within the VZ regulate both the proliferation and ultimate identity of cortical progenitors. The experiments proposed here will elucidate cellular signaling mechanisms within the VZ that are mediated by activation of GABA and glutamate receptors. GABA and glutamate depolarize, increase intracellular calcium concentration, and decrease the synthesis of DNA in the dividing population of cells within the VZ. In the experiments described here, a combination of patch-clamp techniques, calcium imaging, and assays of cell cycle kinetics will be applied to an in vitro explant preparation of developing cerebral cortex in order to further understand the mechanisms by which GABA and glutamate regulate cortical neurogenesis. The specific objectives of the proposed experiments are to (1) identify the circuits in the developing cortex that release the endogenous GABA and glutamate agonists which regulate the cell cycle of VZ cells, (2) specify effects of GABA and glutamate on cell cycle kinetics, and (3) determine whether the rise in intracellular calcium initiated by GABA and glutamate subserves the alterations in cell cycle. The results from these experiments will show how the genesis of neurons in the neocortex is regulated by diffusible signals released from circuits within the developing brain.
