Project 5 - Surmeier (pgs. 187 - 204)

项目 5 - Surmeier（第 187 - 204 页）

• 批准号: 7642295
• 负责人: PAUL GREENGARD
• 金额: $ 37.95万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7642295
• 关键词: Achievement; Antipsychotic Agents; Behavioral; Biochemical; Cells; Clinical; Complement; Corpus striatum structure; Coupled; DARPP 32; Deletion Mutation; Dendrites; Development; Disease; Dopamine D1 Receptor; Functional disorder; GTP-Binding Proteins; Glutamates; Goals; Homologous Gene; Investigation; Ion Channel; Laser Scanning Microscopy; Link; Long-Term Depression; Long-Term Potentiation; Molecular; Molecular Profiling; Morphogenesis; Morphology; Mus; Neurons; Other Resources; Patch-Clamp Techniques; Pattern; Physiological; Prefrontal Cortex; Property; Proteins; Receptor Signaling; Regulation; Resource Development; Schizophrenia; Serotonin; Shapes; Signal Transduction; Slice; Symptoms; Synapses; Synaptic plasticity; Thinking; Tissues; Transgenic Mice; Vertebral column; cell type; computational neuroscience; density; neuropathology; receptor; research study; serotonin receptor; skills; success; transmission process; two-photon; voltage

Neuroleptics that antagonize G-protein coupled, dopaminergic and serotonergic receptors to alleviate the symptoms of schizophrenia. Prolonged treatment with neuroleptics 'remodels' circuits of the prefrontal cortex (PFC) and striatum, ameliorating the symptoms of the disease. It is our central hypothesis is that the induction of remodeling depends upon the ability of neuroleptics to antagonize G-protein coupled, D2, D1, and 5-HT2 receptors, triggering cell-type specific adaptations in striatal and cortical neurons. Neuronal dendrites are likely to be critical targets oi this remodeling, being directly implicated in the schizophrenic neuropathology. D2, D1 and 5-HT.. receptors richly invest dendritic regions of key PFC and striatal neurons and have been implicated in modulating dendritic electrogenesis, synaptic integration and plasticity. Dysregulation of dendritic function by D2, D1 and 5-HTj receptors provides a potential explanation for the apparent involvement of glutamatergic signaling in schi/ophrcnia. Yet, very little is known about how neuroleptics and neuroleptic-sensitive receptors influence dendritic electrogenesis, synaptic integration and plasticity in functionally relevant subpopulations of PFC and striatal neurons. The central goal of the project is to help fill this gap in our understanding. There are two major obstacles blocking achievement of this goal. One obstacle is that the neurons within both the PFC and striatum are heterogeneous in their expression of neuroleptic-sensitive GPCRs. The recent development of BAC transgenic mouse lines in which neurons expressing D2 and D1 receptors are fluoresccntly tagged has effectively removes this obstacle. Another major obstacle is the inaccessibility of dendritic regions to physiological study. The recent development of two photon laser scanning microscopy (2PLSM), when used in conjunction with patch clamp techniques, diminishes this obstacle, opening these critical dendritic regions to investigation. This proposal takes full advantage of these new developments to complement our skills in single cell molecular profiling, electrophysiological analysis of ion channel modulation and computational neuroscience to pursue three specific aims: Specific aim 1 is to characterize, in identified PFC and striatal neurons, short- and long-term neuroleptic-induced adaptations in i:he expression and modulation of voltage dependent ion channels thought to control dendritic electrogenesis. Specific Aim 2 is to characterize short- and long-term neuroleptic-induced adaptations in D2, D1, and 5-HT2 receptor modulation of dendritic electrogenesis and glutamatergic synaptic integration in identified PFC' and striatal neurons. Specific Aim 3 is to characterize in identified PFC and striatal neurons short- and long-term neuroleptic-induced adaptations in dopaminergic modulation of glutamatergic synaptic plasticity. For each of these aims, pursuit of the adaptations will be tightly linked to the other studies proposed in this Conte Center, providing a physiological complement to the molecular, biochemical and behavioral approaches they employ.

拮抗G蛋白偶联、多巴胺能和多巴胺能受体以缓解症状的抗精神病药 精神分裂症长时间的抗精神病药物治疗“重塑”了前额叶皮层（PFC）和纹状体的回路， 改善疾病的症状。我们的中心假设是，诱导重塑取决于 当神经安定药能够拮抗G蛋白偶联的D2、D1和5-HT 2受体，触发细胞类型时， 纹状体和皮层神经元的特殊适应。神经元树突可能是这方面的关键目标 重塑，直接涉及精神分裂症的神经病理学。D2、D1和5-HT..受体丰富地投资 关键PFC和纹状体神经元的树突区域，并且与调节树突电发生有关， 突触整合和可塑性。D2、D1和5-HT 1受体对树突功能的失调提供了一种新的治疗方法。 对schi/ophrcnia中神经递质信号明显参与的潜在解释。然而，我们所知甚少 关于神经抑制剂和神经抑制剂敏感受体如何影响树突电发生，突触整合和 前额叶皮质和纹状体神经元功能相关亚群的可塑性。 该项目的中心目标是帮助填补我们理解中的这一空白。有两大障碍阻碍 实现这一目标。一个障碍是PFC和纹状体内的神经元在其功能上是异质的。 抗精神病药敏感的GPCR的表达。本文综述了近年来BAC转基因小鼠的研究进展， 荧光标记表达D2和D1受体的神经元有效地消除了这一障碍。另一 主要的障碍是树突区域对生理学研究的不可接近性。两个最近的发展 光子激光扫描显微镜（2 PLSM），当与膜片钳技术结合使用时，减少了这一点 障碍，开放这些关键的树突状区域进行研究。该提案充分利用了这些新的 发展，以补充我们在单细胞分子分析，离子通道电生理分析， 调制和计算神经科学追求三个具体目标：具体目标1是表征， 确定PFC和纹状体神经元，短期和长期神经阻滞剂诱导的适应性i：he表达， 电压依赖性离子通道的调节被认为控制树突状细胞的电发生。具体目标二是 描述短期和长期抗精神病药诱导的树突状细胞D2、D1和5-HT 2受体调节适应 在已鉴定的PFC和纹状体神经元中的电发生和突触能突触整合。具体目标3是 表征已鉴定的PFC和纹状体神经元短期和长期神经抑制剂诱导的适应， 多巴胺能调节多巴胺能突触可塑性。对于这些目标中的每一个，追求适应将是 与孔蒂中心提出的其他研究密切相关，为 分子、生物化学和行为学方法。