Synaptic Plasticity of Hypothalamic Neurons

描述(申请人提供)：下丘脑中的巨细胞神经内分泌细胞负责合成和释放加压素和催产素，以及参与液体平衡、血压调节、分娩和哺乳的神经激素。这些神经元的大部分突触调节受神经递质谷氨酸、GABA和去甲肾上腺素的控制。解剖学研究表明，在脱水条件下，大细胞神经分泌系统经历了戏剧性的神经元-神经胶质和突触重组，代表了成人大脑中一种独特的生理联系的结构可塑性模型。这包括大细胞神经元周围的胶质突起的广泛回缩和新的谷氨酸、GABA能和去甲肾上腺素能突触的形成。我们推测，这些结构变化导致大细胞神经元谷氨酸、GABA和去甲肾上腺素能突触输入增加，转运蛋白介导的清除减少，导致环境中这些神经递质的细胞外水平增加。我们将通过比较未经处理和脱水的大鼠对视上核大细胞神经元的谷氨酸和GABA能突触输入的水平，以及环境神经递质水平激活突触前代谢性受体对这些输入的调节来检验第一个假说。我们推测，谷氨酸表达的变化可能与脱水引起的结构可塑性的诱导有关，因为这些受体参与了与发育中和成年脑的结构可塑性相关的突触接触的形成和稳定。我们将通过评估脱水诱导的特定谷氨酸受体亚单位表达的变化，以及通过体内病毒传递特定受体亚单位基因改变正常动物的亚单位表达来检验这一假设。这些研究旨在实现两个目标：1)确定脱水引起的神经元-神经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，并将提供对这些变化的分子机制的洞察。

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.