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合成和释放加压素和催产素，这些神经激素参与体液平衡、血压调节、分娩和哺乳。这些神经元的大部分突触调节是在神经递质谷氨酸、GABA和去甲肾上腺素的控制下。解剖学研究表明，大细胞神经分泌系统在脱水条件下经历戏剧性的神经元-神经胶质和突触重组，代表了成人大脑中生理学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胶质过程的广泛回缩和新的谷氨酸能、GABA能和去甲肾上腺素能突触的形成。我们推测，这些结构的变化导致谷氨酸，GABA和去甲肾上腺素能突触输入的大细胞神经元的增加，以及减少其转运介导的清除，导致这些神经递质的周围细胞外水平的增加。我们将测试这第一个假设，通过比较在未经处理的和脱水的大鼠视上核的大细胞神经元的GABA能和GABA能突触输入的水平，以及这些输入的调制通过激活突触前代谢型受体周围的神经递质水平。我们认为谷氨酸表达的变化可能是脱水引起的结构可塑性诱导的原因，因为这些受体参与了发育和成人大脑中与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亚单位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-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，以及2）确定谷氨酸受体表达的变化是否是诱导脱水相关结构变化的原因。这些研究的成功完成将揭示在脱水条件下观察到的解剖学变化的生理意义，并将提供对这些变化的分子机制的见解。

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.