GABA--EXCITATORY TRANSMITTER IN DEVELOPING HYPOTHALAMUS

描述(调查人员摘要)：这是一项测试 关于GABA在发育中起兴奋作用的普遍假设 大鼠的下丘脑，而不是它被接受的作用 成人的抑制性神经递质。融合方法利用 Fura-2数字钙成像、免疫细胞化学和全细胞贴片 钳位记录将使用培养的神经元来检验五个特定的假设 或者下丘脑片。首先，假设GABA是为了去极化 膜，增加神经元活性，增加细胞内钙离子 在发展的早期，但不是晚期。其次，有人建议 谷氨酸介导的突触活动加速大鼠脑内神经元的成熟 在成人中可见GABA的抑制作用。第三，PI将测试 GABA是否在下丘脑早期合成和释放 发展。第四，GABA被提出用来促进细胞存活， 增加突触发生，影响细胞运动，增加轴突 在早期发育阶段的生长。最后，做一些抑制作用。 神经细胞损伤后，成人体内的GABA恢复抑制作用？ 这种逆转可能会对神经元的反应产生重要的影响 对钙介导的毒性以及它们对GABA的一般反应。 由于下丘脑的许多环路是抑制的，并由GABA介导 成年后，GABA的早期兴奋作用可能对正常 发展。

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.