REGULATION OF TRANSMISSION BY PRESYNAPTIC RECEPTORS

描述：复杂动作的精确执行源于 来自初级传入神经元和皮质脊髓的直接输入的会聚 投射到运动神经元，以及来自脊髓的间接输入 中间神经元。 突触传递的突触前调制是一种 这个电路的重要组成部分。 初步研究， 脊髓半切表明突触前烟碱乙酰胆碱 受体（nAChR）增强对脊髓运动神经元的兴奋性突触输入。 本提案的目标是审查生物物理机制， nAChR介导的突触增强的基础受体成分 在脊髓中传播。 突触前nAChRs的初步测定 将评估自发和诱发突触传递的变化， 运动神经元的记录。 在最初的研究中， 通过nAChR的传递将在两个半完整的制备物中进行检查， 横切片和半切脊髓，在条件下， 模仿原生环境。 nAChR作用的表征 激活诱发传输将能够识别 表达这些受体的传入输入的类别。 这些发现 将指导分离运动神经元的培养， 由适当的传入输入的外植体支配。 使用这些 共培养，更详细的分子，药理学和生物物理学 将对调节每种类型的突触前nAChR进行分析。 运动神经元的传入输入。 这项建议还将审查 内源性释放乙酰胆碱对突触前nAChRs和突触的影响 功效 突触前nAChR的内源性激活将通过以下方式实现： 刺激所研究的运动神经元以引起ACh的局部释放。 最后，乙酰胆碱酯酶抑制剂的作用， 负责消除ACh释放后，也将是 考察 总的来说，这些研究将提供详细的 受体的药理学、分子和生物物理学分析 参与nAChR介导的突触前兴奋性增强的亚型 在脊髓中传播。 这些研究将大大推进 我们对影响运动神经元兴奋性的因素的理解， 希望能找到新的方法来减轻衰弱的症状， 与运动和感觉神经元的退行性疾病有关。

DESCRIPTION: The precise execution of complex movements results from the convergence of direct input from primary afferent neurons and corticospinal projections onto motoneurons, as well as indirect inputs from spinal cord interneurons. Presynaptic modulation of synaptic transmission is an important component of this circuitry. Preliminary studies in the hemisected spinal cord indicate that presynaptic nicotinic acetylcholine receptors (nAChRs) enhance excitatory synaptic inputs to spinal motoneurons. The goal of this proposal is to examine the biophysical mechanisms and receptor components that underlie nAChR-mediated enhancement of synaptic transmission in the spinal cord. The primary assay of presynaptic nAChRs will assess changes in the spontaneous and evoked synaptic transmission in recordings from motoneurons. In initial studies, the modulation of synaptic transmission by nAChRs will be examined in two semi-intact preparations, transverse slices and hemisected spinal cord, under conditions that closely mimic the native environment. Characterization of the effects of nAChR activation on evoked transmission will enable identification of the class(es) of afferent inputs that express these receptors. These findings will then guide the making of cultures of dissociated motoneurons that are innervated by explants of the appropriate afferent inputs. Using these cocultures, more detailed molecular, pharmacological and biophysical analyses will be made of the presynaptic nAChRs that modulate each type of afferent inputs to motoneurons. This proposal will also examine the influence of endogenously released ACh on presynaptic nAChRs and synaptic efficacy. Endogenous activation of presynaptic nAChRs will be achieved by stimulating the motoneuron under study to evoke a local release of ACh. Finally, the effects of inhibitors of acetylcholine esterase, the enzyme that is responsible for eliminating ACh after its release, will also be examined. Collectively, these studies will provide a detailed pharmacological, molecular, and biophysical analysis of the receptor subtypes involved in nAChR-mediated presynaptic enhancement of excitatory transmission in the spinal cord. These studies will significantly advance our understanding of the factors that influence motoneuron excitability and hopefully identify new approaches to alleviating the debilitating symptoms associated with degenerative diseases of motor and sensory neurons.