Pathology in postmortem schizophrenic basal ganglia

描述（由申请人提供）：这是一个研究精神分裂症受试者（SZ）死后纹状体突触组织超微结构水平的项目的修订竞争更新。纹状体与其他大脑区域相互作用，影响运动、认知和边缘系统行为，是精神分裂症受影响的区域之一。上一个资助周期的研究结果表明，尾状核基质和壳核斑块中的皮质-纹状体型突触增加，这不是由抗精神病药物引起的。SZ病例皮质型突触的密度高于对照组，提示纹状体投射神经元的过度刺激。这可能有几个重要的和不同的下游影响，这取决于所涉及的精确电路。本申请试图鉴定SZ中受影响的特定纹状体回路。SA#1）为了验证边缘系统和前额叶回路在纹状体水平受到干扰的假设，我们将检查处理这些回路的纹状体子区域中的突触密度。SA 2将检查SA 1中确定的选择纹状体区域中的贴片和基质中的纹状体黑质和纹状体苍白球神经元的突触密度。SA#2A）为了检验尾状核中的纹状体苍白球基质神经元接收更多兴奋性输入的假设，将进行脑啡肽（这些神经元的标记物）的免疫细胞化学定位;将在组之间比较在标记的棘上形成的突触的数量。SA#2B）测试尾状核中的纹状体黑质基质神经元接收更多兴奋性输入，但壳核斑中的纹状体黑质神经元接收正常或较少数量的突触的假设。将进行P物质（纹状体黑质神经元的标记物）的免疫细胞化学定位;将比较组间标记棘上形成的突触数量。SA#3）为了检验典型APD与非典型APD对贴片和基质隔室具有不同影响的假设，我们将用APD长期治疗大鼠，处理组织进行钙结合蛋白免疫细胞化学，以鉴定贴片和基质，并分析从每种贴片和基质中获得的EM样品。在从刘易斯博士处获得的猴组织中，我们将使用光学显微镜检查长期氟哌啶醇给药动物和对照动物的贴片和基质隔室中的突触密度（用突触素标记）。拟议的实验将：1）区分药物作用和突触病理学中的疾病相关改变; 2）将提供对抗精神病药物作用机制的深入了解;和3）是鉴定可能是精神分裂症的一些精神病理学基础的假定异常纹状体回路的重要初始步骤。

DESCRIPTION (provided by applicant): This is a revised competing renewal of a project studying the synaptic organization of postmortem striatum in schizophrenic subjects (SZ) at the ultrastructural level. The striatum, which interacts with other brain areas to affect motor, cognitive and limbic behavior, is one of the regions affected in schizophrenia. The results of the studies in the last grant cycle indicated an increase in cortico-striatal type synapses in the caudate matrix and putamen patches, that was not caused by antipsychotic medication. The higher density of cortical-type synapses in the SZ cases than in controls suggests hyper-stimulation of striatal projection neurons. This could have several important and different downstream effects depending on the precise circuitry involved. The present application seeks to identify the specific striatal circuitry affected in SZ. SA#1) To test the hypothesis that limbic and prefrontal circuitry are perturbed at the level of the striatum, we will examine synaptic density in the subregions of the striatum that process these circuits. SA2 will examine synaptic density of striatonigral and striatopallidal neurons in the patch and matrix in select striatal territories determined in SA1. SA#2A) To test the hypothesis that striatopallidal matrix neurons in the caudate receive more excitatory inputs, the immunocytochemical localization of enkephalin, a marker of these neurons, will be performed; the number of synapses formed onto labeled spines will be compared between groups. SA#2B) Tests the hypotheses that striatonigral matrix neurons in the caudate receive more excitatory inputs, but that striatonigral neurons in the putamen patch receive normal or fewer numbers of synapses. The immunocytochemical localization of substance P, a marker of striatonigral neurons, will be performed; the number of synapses formed onto labeled spines will be compared between groups. SA#3) To test the hypothesis that typical vs atypical APDs have different effects on the patch and matrix compartment, we will treat rats chronically with APDs, process the tissue for calbindin immunocytochemistry to identify the patch and matrix and analyze EM samples obtained from each. In monkey tissue obtained from Dr. Lewis, we will examine the synaptic density (labeled with synaptophysin) within the patch and matrix compartments in chronic haldol treated animals and controls using light microscopy. The proposed experiments will: 1) distinguish between drug effects and disease related alterations in synaptic pathology; 2) will provide insight into the mechanisms of action of antipsychotic drugs; and 3) are an important initial step in identifying putative abnormal striatal circuitry that may underlie some of the psychopathology of schizophrenia.