Cellular Adaptations to Neuroleptic Treatment in the Dorsal Striatum

描述（由申请人提供）：精神分裂症影响全球1%的人口;尽管对姑息性症状补救的机制不完全了解，但神经安定（抗精神病药）药物对治疗至关重要。尽管对多巴胺2受体（D2 R）和多巴胺能外效应的拮抗程度不同，但典型的神经安定药（例如氟哌啶醇）和精神安定药（例如氯氮平）都能有效地长期重塑皮质纹状体突触，这是疾病病理生理学和药理学活性的主要部位，如体内成像和死后组织分析所证明的。以前的研究一直受到阻碍，无法实验分离纹状体中的异质细胞群，并从树突状突起的索马分辨率不足。在多巴胺1受体（D1 R）和D2 R启动子下表达eGFP的BAG转基因小鼠将用于区分纹状体中的二分主神经元群体，结合双光子激光扫描显微镜（2 PLSM）以深入了解树突功能。由于对慢性精神抑制剂给药的适应在正常与患病状态下可能不同，RGS 4敲除小鼠将被用作与野生型菌株平行的精神分裂症样模型; RGS 4在可证实的遗传传递的情况下被认为是精神分裂症易感基因，并且在帕金森病动物模型的纹状体中对改变的多巴胺传递敏感。总之，本提案旨在表征临床药理学中药效学改善的复合效应。将使用全细胞膜片钳电生理学，结合分子转基因、药理学和双光子成像模式，研究亚慢性典型（即氟哌啶醇）和非典型（即氯氮平）抗精神病药给药后野生型和RGS 4敲除小鼠背侧纹状体中神经元亚群的重塑。具体目标1将检查背侧纹状体中棘神经元的内在，形态和树突特性。为了评估前额叶皮层和纹状体神经元之间的功能连接，具体目标2将针对皮质纹状体突触中的突触前和突触后调整。

DESCRIPTION (provided by applicant): Schizophrenia affects 1% of the population worldwide; neuroleptic (antipsychotic) medications are essential for treatment despite an incomplete understanding of the mechanisms through which palliative symptomatic remediation is exerted. Though different in the degree of antagonism for the dopamine 2 receptor (D2R) and extradopaminergic effects, both 'typical1 neuroleptics (e.g. haloperidol) and 'atypical1 neuroleptics such as clozapine are effective at long-term remodeling of the corticostriatal synapse, a primary site of disease pathophysiology and pharmacotherapeutic activity as demonstrated by in vivo imaging and postmortem tissue analyses. Previous study has been impeded by an inability to experimentally separate a heterogeneous cell population in the striatum, and by inadequate resolution from the soma of dendritic processes. BAG transgenic mice expressing eGFP under the dopamine 1 receptor (D1R) and D2R promoters will be used to distinguish dichotomous principal neuron populations in the striatum, in combination with 2-photon laser scanning microscopy (2PLSM) to gain insight into dendritic function. As adaptations to chronic neuroleptic administration may be different in normal versus diseased states, an RGS4 knockout mouse will be employed as a schizophrenic-like model in parallel to wildtype strains; RGS4 has been implicated as both a schizophrenia susceptibility gene in cases of demonstrable hereditary transmission and a gene sensitive to altered dopamine transmission in the striatum of Parkinsonian animal models. In summary, this proposal aims to characterize the compound effect by which pharmacotherapeutic improvement in clinical symptomatology is effected. Whole-cell patch clamp electrophysiology, combined with molecular transgenic, pharmacologic, and 2-photon imaging modalities will be used to study the remodeling of neuronal subpopulations in the dorsal striatum of wildtype and RGS4 knockout mice following subchronic typical (i.e. haloperidol) and atypical (i.e. clozapine) neuroleptic administration. Specific Aim 1 will examine the intrinsic, morphologic, and dendritic properties of medium spiny neurons of the dorsal striatum. To assess functional connectivity between prefrontal cortical and striatal neurons, Specific Aim 2 will target presynaptic and postsynaptic adjustments in the corticostriatal synapse.