REGULATION OF TRANSMISSION BY PRESYNAPTIC RECEPTORS

描述：复杂动作的精确执行源于 初级传入神经元和皮质脊髓的直接输入的汇聚 向运动神经元的投射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 是这个电路的重要组成部分。初步研究在 脊髓半横断表明突触前烟碱型乙酰胆碱 受体(NAChRs)增强对脊髓运动神经元的兴奋性突触输入。 这项建议的目标是检查生物物理机制和 NAChR介导突触增强的受体成分 在脊髓中的传播。突触前nAChRs的初步测定 将评估自发性和诱发性突触传递的变化 运动神经元的录音。在最初的研究中，突触的调制 NAChRs的传播将在两种半完整的制剂中进行检查， 横切片和半横断脊髓，在接近的条件下 模仿原生环境。NAChR作用的表征 对诱发传输的激活将使识别 表达这些受体的传入输入的类别。这些发现 将指导培养分离的运动神经元，这些神经元是 由适当的传入输入的外植体所支配。使用这些 共培养，更详细的分子、药理和生物物理 将对调节每种类型的突触前nAChRs进行分析 运动神经元的传入输入。这项提案还将审查 内源性ACh释放对突触前nAChRs和突触的影响 功效。突触前nAChRs的内源性激活将通过 刺激被研究的运动神经元以引起局部ACh的释放。 最后，乙酰胆碱酯酶抑制剂的作用 负责在ACh发布后消除它的，也将是 检查过了。总体而言，这些研究将提供详细的 受体的药理、分子和生物物理分析 NAChR介导的突触前兴奋性增强的亚型 在脊髓中的传播。这些研究将大大推进 我们对影响运动神经元兴奋性和 希望找到新的方法来缓解虚弱的症状 与运动神经元和感觉神经元退行性疾病有关。

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.