Cellular Adaptations to Neuroleptic Treatment in the Dorsal Striatum

描述(申请人提供)：精神分裂症影响全球1%的人口；尽管对实施姑息症状补救的机制了解不完全，但抗精神病药物仍是治疗的基本药物。尽管对多巴胺2受体(D2R)和多巴胺能外效应的拮抗程度不同，但典型的1类抗神经药(如氟哌啶醇)和非典型的1类抗神经药如氯氮平在皮质纹状体突触的长期重塑方面都有效，活体成像和死后组织分析表明，皮质纹状体突触是疾病病理生理和药物治疗活性的主要部位。之前的研究由于无法在实验上分离纹状体中的异质细胞群，以及不能从树突的胞体中分离出来而受阻。在多巴胺1受体(D1R)和D2R启动子下表达EGFP的BAG转基因小鼠将被用来区分纹状体中的二分主神经元群，并结合双光子激光扫描显微镜(2PLSM)来深入了解树突状细胞的功能。由于对长期服用抗精神病药物的适应在正常和疾病状态下可能不同，RGS4基因敲除小鼠将被用作精神分裂症样模型和野生型菌株；RGS4被认为是帕金森病动物模型纹状体中对改变多巴胺传递敏感的基因和精神分裂症易感基因。综上所述，这项建议旨在描述临床症状学药物治疗改善的复合效应。我们将利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技术，研究亚慢性典型(即氟哌啶醇)和非典型(即氯氮平)抗精神病药物治疗后野生型和RGS4基因敲除小鼠背侧纹状体神经元亚群的重构。具体目标1将研究背侧纹状体中棘神经元的内在、形态和树突特性。为了评估前额叶皮质和纹状体神经元之间的功能连接，特定目标2将针对皮质纹状体突触的突触前和突触后调节。

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.