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缓解精神分裂症的症状。抗精神病药物的长期治疗“重塑”了前额叶皮层和纹状体的回路，改善了疾病的症状。我们的中心假设是，这种重塑依赖于抗精神病药物的能力，触发细胞类型的特定适应突触连接，树突状结构和内在的纹状体和皮层神经元的兴奋性。这些关键的调节失调 亚细胞区域可能是精神分裂症的中心因素，并提供了与疾病中的代谢能决定因素的明显联系。然而，很少有人知道抗精神病药物和抗精神病药物敏感的受体如何影响树突状电，突触整合和可塑性功能相关的纹状体和PFC神经元亚群。该项目的中心目标是帮助填补我们理解中的这一空白，但是，要成功还有障碍。其一是纹状体和PFC内的神经元是异质的。另一个主要的障碍是树突状区域无法进行生理学研究。该方案利用BAC转基因小鼠、双光子激光扫描显微镜和双光子激光开瓶的发展来克服这些障碍。这些方法将与电生理学、药理学和分子学策略结合使用，以补充该Conte中心的其他项目，以实现三个具体目标：1）描述抗精神病药物治疗对两个主要细胞的体树突兴奋性和形态学的影响。 纹状体的类型：2）描述抗精神病药物治疗对从大脑皮层和丘脑到纹状体MSNs的两个主要输入所形成的突触性质的影响; 3）描述抗精神病药物治疗对体树突形态和确定的边缘前/边缘下（PL/IL）皮层锥体神经元亚群的兴奋性的影响。