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死后纹状体突触组织的项目的修订竞争性更新。纹状体与大脑其他区域相互作用，影响运动、认知和边缘行为，是精神分裂症中受影响的区域之一。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。在SZ病例中，皮质型突触的密度高于对照组，这表明纹状体投射神经元受到了过度刺激。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。目前的应用程序旨在确定特定纹状体回路影响SZ。为了验证边缘和前额叶回路在纹状体水平上受到干扰的假设，我们将检查处理这些回路的纹状体亚区域的突触密度。SA2将检测纹状体斑块和基质中纹状体区域的纹状体和纹状顶神经元的突触密度。SA#2A)为了验证尾状核中的纹状体基质神经元接受更多兴奋性输入的假设，将对这些神经元的标记物脑啡肽进行免疫细胞化学定位；在标记的脊椎上形成的突触数量将在组间进行比较。SA#2B)验证了尾状核的纹状体基质神经元接受更多兴奋性输入，但壳核斑块的纹状体神经元接受正常或更少数量的突触的假设。将进行纹状体神经元标记物P物质的免疫细胞化学定位；在标记的脊椎上形成的突触数量将在组间进行比较。SA#3)为了验证典型apd与非典型apd对贴片和基质室有不同影响的假设，我们将对长期患有apd的大鼠进行治疗，对组织进行钙结合蛋白免疫细胞化学处理，以识别贴片和基质，并分析从中获得的EM样本。在Lewis博士提供的猴子组织中，我们将使用光学显微镜检查慢性氟哌啶醇治疗动物和对照动物的斑块和基质室内的突触密度（用synaptophysin标记）。提出的实验将：1)区分药物作用和突触病理中疾病相关的改变；2)深入了解抗精神病药物的作用机制；3)是识别纹状体电路异常的重要初始步骤，纹状体电路异常可能是精神分裂症的一些精神病理的基础。

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.