Antipsychotic-induced Adaptations in the Somatodendritic and Synaptic Physiology

抗精神病药物可以拮抗G蛋白，多巴胺能受体可以缓解精神分裂症的症状。长期使用抗精神病药物重塑前额叶皮质和纹状体的回路，改善疾病的症状。我们的中心假设是，这种重塑依赖于抗精神病药物在纹状体和皮质神经元的突触连接、树突结构和内在兴奋性方面触发细胞型特异性适应的能力。这些关键因素的失调 亚细胞区可能是精神分裂症的中心因素，并与疾病中的谷氨酸能决定因素有明显的联系。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树突电发生、突触整合和纹状体和PFC神经元功能相关亚群的可塑性，人们知之甚少。该项目的中心目标是帮助填补我们在理解上的这一差距，但成功存在障碍。其一，纹状体和前额叶皮质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学研究。这一建议利用BAC转基因小鼠、双光子激光扫描显微镜和双光子激光消融的发展来克服这些障碍。这些方法将与电生理学、药理学和分子策略相结合，作为本中心其他项目的补充，以实现三个具体目标：1)表征抗精神病药物治疗对两个主要细胞的躯体树突状细胞兴奋性和形态的影响 目的：1)研究抗精神病药治疗对纹状体黑质和纹状体中棘神经元(MSN)的影响；2)研究抗精神病药物治疗对大脑皮质和丘脑向纹状体MSN的两种主要输入所形成的突触特性的影响；3)研究抗精神病药物治疗对已鉴定的前缘/下缘(PL/IL)皮质锥体神经元亚群的躯体树突形态和兴奋性的影响。

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.