A variety of developmental disorders with seizures as a manifestation have their origin at early stages of corticogenesis, ranging from major birth defects to subtle cortical heterotopias. Recent data points to the importance of environmental signals in the embryonic ventricular zone as critical to establishing the ultimate fate of cortical neurons. The physiological properties of the neocortical precursor cells in the embryonic ventricular zone remain relatively unknown. Recent findings from this laboratory reveal that cells in the ventricular zone communicate with each other through gap junction channels and respond to changes in their environment through amino acid receptors for GABA and glutamate, well in advance of synapse formation. Moreover, activation of amino acid receptors on ventricular zone cells regulates cell cycle events and the proliferation of cortical neurons. These findings underscore the importance of environmental signals rather than simply cell-autonomous genetic programs in early cortical development. In this proposal, the mechanisms by which the amino acid receptors for GABA and glutamate influence early stages of corticogenesis will be explored in detail. The specific glutamate and GABA receptor subtypes expressed on ventricular zone cells will be identified based on physiological and pharmacological properties using in Situ patch clamp recording of whole-cell currents and analysis of channel properties in excised membrane patches. These studies will complement recent molecular information concerning the developmental expression patterns of GABA and glutamate receptor subtypes that suggest receptors with unique physiological properties are expressed in embryonic stages. The mechanism by which receptor activation alters cell proliferation will be studied in detail, including the possible role of second messengers. The significance of amino acid-induced changes in intracellular calcium ([Ca++],) level will be explored through the use of (Ca++]i level measurements in living cortical explants. These experiments will begin to illuminate how amino acid transmitters in the embryonic neocortex influence critical events in early corticogenesis.
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