Pathology in postmortem schizophrenic basal ganglia

描述(由申请人提供)：这是一个在超微结构水平上研究精神分裂症受试者(SZ)死后纹状体突触组织的项目的修订竞争更新。纹状体是精神分裂症中受影响的区域之一，它与其他大脑区域相互作用，影响运动、认知和边缘行为。上一次赠款周期的研究结果表明，尾状核基质和壳核贴片中的皮质纹状体类型突触增加，这不是由抗精神病药物引起的。SZ组皮质型突触密度高于对照组，提示纹状体投射神经元受到过度刺激。这可能会产生几个重要且不同的下游影响，具体取决于所涉及的精密电路。本申请旨在确定SZ中受影响的特定纹状体回路。SA#1)为了验证边缘和前额叶回路在纹状体水平受到干扰的假设，我们将检查纹状体处理这些回路的亚区的突触密度。SA2将检测在SA1中确定的选定纹状体区域的斑块和基质中纹状体黑质和纹状体苍白质神经元的突触密度。SA#2A)为了验证这样一种假设，即尾状核中的纹状体-桥本基质神经元接受更多的兴奋性输入，将进行脑啡肽的免疫细胞化学定位，脑啡肽是这些神经元的标记物；将比较不同组之间形成在标记脊髓上的突触的数量。SA#2B)验证了这样的假设，即尾状核中的纹状体黑质基质神经元接受更多的兴奋性输入，但壳核斑块中的纹状体黑质神经元获得正常或更少数量的突触。将进行P物质的免疫细胞化学定位，这是纹状体黑质神经元的标志；将比较不同组之间形成的标记脊髓上的突触数量。SA#3)为了验证典型和非典型APD对贴片和基质间隔室有不同影响的假设，我们将对患有APDS的大鼠进行慢性治疗，对组织进行钙结合素免疫细胞化学处理，以识别贴片和基质，并分析从每个组织获得的EM样本。在从刘易斯博士获得的猴子组织中，我们将使用光学显微镜检查慢性氟多尔治疗的动物和对照组的斑块和基质隔间内的突触密度(用突触素标记)。拟议的实验将：1)区分药物效应和突触病理中与疾病相关的变化；2)将为抗精神病药物的作用机制提供洞察；以及3)是识别可能是精神分裂症一些精神病理基础的假定异常纹状体回路的重要的第一步。

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.