Synaptic Plasticity of Hypothalamic Neurons

描述（由申请人提供）：下丘脑中的大细胞神经内分泌细胞负责加压素和催产素的合成和释放，这些神经激素参与体液平衡、血压调节、分娩和哺乳。这些神经元的突触调节大部分受神经递质谷氨酸、氨基丁酸和去甲肾上腺素的控制。解剖学研究表明，大细胞神经分泌系统在脱水条件下经历了戏剧性的神经元-胶质和突触重组，代表了成人大脑中生理相关结构可塑性的独特模型。这包括从大细胞神经元周围的神经胶质过程的广泛收缩和新的谷氨酸能、氨基丁酸能和去甲肾上腺素能突触的形成。我们假设这些结构变化导致大细胞神经元的谷氨酸、GABA和去甲肾上腺素能突触输入增加，以及它们的转运体介导的清除减少，从而导致这些神经递质的细胞外环境水平增加。我们将通过比较未处理大鼠和脱水大鼠视上核大细胞神经元的谷氨酸能和氨基丁酸能突触输入水平，以及环境神经递质水平激活突触前代谢受体对这些输入的调节，来验证第一个假设。我们假设谷氨酸表达的变化可能是导致脱水引起的结构可塑性的原因，因为这些受体与发育和成年大脑中与结构可塑性相关的突触接触的形成和稳定有关。我们将通过评估脱水诱导的特定谷氨酸受体亚基表达的变化，以及通过病毒在体内传递特定受体亚基基因来改变正常动物的亚基表达，来验证这一假设。这些研究旨在实现两个目标：1)确定脱水诱导的神经元-胶质结构变化是否导致突触神经支配和大细胞神经元兴奋性的变化；2)确定谷氨酸受体表达的变化是否导致与脱水相关的结构变化。这些研究的成功完成将揭示在脱水条件下观察到的解剖变化的生理意义，并将为这些变化的分子机制提供见解。

DESCRIPTION (provided by applicant): Magnocellular neuroendocrine cells in the hypothalamus are responsible for the synthesis and release of vasopressin and oxytocin, neurohormones involved in fluid balance, blood pressure regulation, parturition and lactation. Much of the synaptic regulation of these neurons is under the control of the neurotransmitters glutamate, GABA and norepinephrine. Anatomical studies have shown that the magnocellular neurosecretory systems undergo dramatic neuronal-glial and synaptic reorganization under conditions of dehydration, representing a unique model of physiologically linked structural plasticity in the adult brain. This includes extensive retraction of glial processes from around the magnocellular neurons and the formation of new glutamatergic, GABAergic and noradrenergic synapses. We postulate that these structural changes lead to an increase in the glutamate, GABA and noradrenergic synaptic inputs to the magnocellular neurons as well as to a decrease in their transporter-mediated clearance, resulting in an increase in the ambient extracellular levels of these neurotransmitters. We will test this first hypothesis by comparing in untreated and dehydrated rats the levels of glutamatergic and GABAergic synaptic inputs to magnocellular neurons of the supraoptic nucleus, as well as the modulation of these inputs by activation of presynaptic metabotropic receptors by ambient neurotransmitter levels. We posit that changes in the expression of glutamate may be responsible for the induction of the structural plasticity caused by dehydration, as these receptors have been implicated in the formation and stabilization of synaptic contacts associated with structural plasticity in developing and adult brain. We will test this hypothesis by assessing dehydration-induced changes in the expression of specific glutamate receptor subunits, and by altering subunit expression in normal animals through viral delivery of specific receptor subunit genes in vivo. These studies are designed to accomplish two goals: 1) to determine whether the neuronal-glial structural changes induced by dehydration lead to changes in the synaptic innervation and in the excitability of magnocellular neurons, and 2) to determine whether changes in glutamate receptor expression are causal in the induction of the structural changes associated with dehydration. The successful completion of these studies will reveal the physiological significance of anatomical changes observed under conditions of dehydration, and will provide insight into the molecular mechanisms responsible for these changes.