Antipsychotic-induced Adaptations in the Somatodendritic and Synaptic Physiology

抗精神病药物诱导的体细胞树突和突触生理学适应

• 批准号: 8150129
• 负责人: DALTON JAMES SURMEIER
• 金额: $ 27.02万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150129
• 关键词: Affect; Antipsychotic Agents; Architecture; Axon; Brain; Cerebral cortex; Clozapine; Complement; Corpus striatum structure; Coupled; Disease; Electric Stimulation; Electrophysiology (science); GTP-Binding Proteins; Glutamates; Goals; Haloperidol; Laser Scanning Microscopy; Lasers; Mental disorders; Molecular; Morphology; Neurons; Physiological; Physiology; Population; Prefrontal Cortex; Probability; Property; Public Health; Schizophrenia; Slice; Symptoms; Synapses; Thalamic structure; Transgenic Mice; cell type; hippocampal pyramidal neuron; insight; mouse development; patch clamp; receptor; success; therapy development; two-photon

Antipsychotics that antagonize G-protein coupled, dopaminergic receptors alleviate the symptoms of schizophrenia. Prolonged treatment with antipsychotics 'remodels' circuits of the prefrontal cortex and striatum, ameliorating the symptoms of the disease. Our central hypothesis is that this remodeling depends upon the ability of antipsychotics to trigger cell-type specific adaptations in the synaptic connectivity, dendritic architecture and intrinsic excitability of striatal and cortical neurons. Dysregulation of these key sub-cellular regions is likely to be a central factor in schizophrenia and provides an obvious linkage to glutamatergic determinants in the disease. Yet, little is known about how antipsychotics and antipsychotic-sensitive receptors influence dendritic electrogenesis, synaptic integration and plasticity in functionally relevant subpopulations of striatal and PFC neurons. The central goal of the project is to help fill this gap in our understanding, but, there are obstacles to success. One is that the neurons within both the striatum and PFC are heterogeneous. Another major obstacle is the inaccessibility of dendritic regions to physiological study. This proposal takes advantage of BAC transgenic mice, the development of two photon laser scanning microscopy and two photon laser uncaging to overcome these obstacles. These approaches will be used in conjunction with electrophysiological, pharmacological and molecular strategies that complement the other Projects in this Conte Center to pursue three Specific Aims: 1) To characterize the impact of antipsychotic treatment on somatodendritic excitability and morphology of the two principal cell types in the striatum: striatonigral and striatopallidal medium spiny neurons (MSNs); 2) To characterize the impact of antipsychotic treatment on the properties of synapses formed by the two principal inputs to striatal MSNs from the cerebral cortex and thalamus; 3) To characterize the impact of antipsychotic treatment on the somatodendritic morphology and excitability of identified subsets of prelimbic/infralimbic (PL/IL) cortex pyramidal neurons.

拮抗 G 蛋白偶联多巴胺能受体的抗精神病药可减轻精神分裂症的症状。长期使用抗精神病药物治疗可以“重塑”前额皮质和纹状体的回路，从而改善疾病的症状。我们的中心假设是，这种重塑取决于抗精神病药物触发纹状体和皮质神经元的突触连接、树突结构和内在兴奋性的细胞类型特异性适应的能力。这些关键的失调 亚细胞区域可能是精神分裂症的核心因素，并与该疾病中的谷氨酸决定因素存在明显的联系。然而，关于抗精神病药物和抗精神病药物敏感受体如何影响纹状体和 PFC 神经元功能相关亚群的树突电发生、突触整合和可塑性，人们知之甚少。该项目的中心目标是帮助填补我们理解上的这一空白，但是，成功也存在障碍。一是纹状体和前额皮层内的神经元是异质的。另一个主要障碍是树突区域无法进行生理研究。该提案利用BAC转基因小鼠的优势，开发了二光子激光扫描显微镜和二光子激光解笼器来克服这些障碍。这些方法将与电生理学、药理学和分子策略结合使用，补充该 Conte 中心的其他项目，以实现三个具体目标：1) 表征抗精神病药物治疗对两种主要细胞的体树突兴奋性和形态的影响 纹状体类型：纹状体黑质和纹状体苍白质中型多棘神经元 (MSN)； 2) 表征抗精神病药物治疗对突触特性的影响，突触特性由来自大脑皮层和丘脑的纹状体 MSN 的两个主要输入形成； 3) 表征抗精神病药物治疗对已识别的边缘前/边缘下 (PL/IL) 皮质锥体神经元亚群的体树突形态和兴奋性的影响。