GABA--EXCITATORY TRANSMITTER IN DEVELOPING HYPOTHALAMUS

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DESCRIPTION (Investigator's Abstract): This is a proposal to test the general hypothesis that GABA plays an excitatory role in the developing hypothalamus of the rat, in contrast to its accepted role as an inhibitory neurotransmitter in the adult. Converging approaches utilizing fura-2 digital calcium imaging, immunocytochemistry and whole cell patch clamp recording will test five specific hypotheses using cultured neurons or hypothalamic slices. First, GABA is hypothesized to depolarize the membrane, increase neuronal activity, and increase intracellular calcium early, but not late, in development. Secondly, it is proposed that glutamate-mediated synaptic activity accelerates the maturation of the inhibitory actions of GABA seen in adults. Thirdly, the PI will test whether GABA is synthesized and released during early hypothalamic development. Fourthly, GABA is proposed to promote cell survival, increase synaptogenesis, influence cell motility, and increase neurite outgrowth in early development. Finally, do the inhibitory actions of GABA in the adult revert to inhibitory actions following neuronal injury? This reversion may have important consequences for how neurons respond to calcium-mediated toxicity and how they respond to GABA in general. Since many hypothalamic circuits are inhibitory and mediated by GABA in the adult, GABA's early excitatory actions may be crucial for normal development.