Restoration of GABAergic function in a Rodent Model of Schizophrenia

描述（由申请人提供）：最近在精神分裂症领域的研究为中边缘多巴胺系统失调的理论提供了支持，该理论被认为是该疾病阳性症状的基础，源于海马体的过度活跃。人类成像研究和啮齿动物疾病模型的实验确实说明了这一现象。我们认为海马体过度活跃是该区域缺乏gaba能抑制控制的结果。与这一假设相一致的是，在患者和啮齿动物模型的整个额皮质和海马中观察到小白蛋白阳性中间神经元的显著减少。具体来说，gaba能中间神经元功能下降可能是海马输出异常的原因。在MAM模型（一种经过验证的精神分裂症妊娠中断模型）中完成的啮齿动物学生表明，通过抑制异常的海马腹侧活动，通过TTX失活，我们观察到多巴胺系统功能的恢复。本研究将采用一种新的方法，将胚胎大鼠内侧神经节隆起的gaba能神经元移植到青春期后经mam治疗的大鼠腹侧海马体中，以恢复腹侧海马体间神经元功能。来自该区域的细胞已被证明分化为成熟的中间神经元，并可能使异常的多巴胺传递和行为正常化，提供了一个新的治疗靶点。我们计划评估MGE细胞移植对mam治疗大鼠的影响，具体目的如下：1)确定GFP+ vHipp gabaergy前体细胞移植对海马腹侧和多巴胺神经元活动的影响；2)确定GFP+ vHipp gabaergy前体细胞移植是否会逆转mam治疗大鼠的阳性、阴性和认知缺陷相关行为。从拟议的研究中收集的数据将为进一步了解这种疾病提供证据，并为精神分裂症的药物干预提供新的靶点。

DESCRIPTION (provided by applicant): Recent studies in the field of schizophrenia have provided support for the theory that dysregulation of the mesolimbic dopamine system, thought to underlie positive symptoms of the disease, stems from hyperactivity of the hippocampus. Human imaging studies and experiments done in rodent models of the disease do indeed illustrate this phenomenon. We believe hippocampal hyperactivity is a result of a lack of GABAergic inhibitory control in this region. Consistent with this hypothesis, a marked decrease of parvalbumin positive interneurons is observed throughout the frontal cortices and hippocampi of patients and rodent models. Specifically, GABAergic interneuron function decreases may be the cause of the aberrant hippocampal output. Rodent students done in the MAM model, a verified gestation disruption model of schizophrenia, demonstrate that by inhibiting aberrant ventral hippocampal activity, via TTX inactivation, we observe a restoration of dopamine system function. Here we will utilize a novel procedure to restore ventral hippocampal interneuron function by transplanting GABAergic neurons from the medial ganglionic eminence of embryonic rats into the ventral hippocampus of post-pubertal MAM-treated rats. Cells from this region have been shown to differentiate into mature interneurons and may act to normalize aberrant dopamine transmission and behaviors, providing a novel therapeutic target. We plan to evaluate the effects of MGE cell transplantation in MAM-treated rats with the following Specific Aims: 1) determining the effects of GFP+ vHipp GABAergic precursor cell transplant on ventral hippocampal and dopamine neuron activity and 2) determining whether GFP+ vHipp GABAergic precursor cell transplant will reverse behaviors associated with the positive, negative, and cognitive deficits seen MAM-treated rats. Data collected from the proposed studies will provide evidence to further understand the disorder, as well as, provide a novel target for the pharmacology intervention of schizophrenia.