Restoration of GABAergic function in a Rodent Model of Schizophrenia

描述（由申请人提供）：精神分裂症领域的最新研究为以下理论提供了支持：中脑边缘多巴胺系统的失调，被认为是该疾病的阳性症状的基础，源于海马体的过度活跃。人类成像研究和在啮齿动物疾病模型中进行的实验确实说明了这一现象。我们认为海马活动过度是由于该区域缺乏GABA能抑制控制的结果。与该假设一致，在患者和啮齿动物模型的整个额叶皮质和大脑中观察到小白蛋白阳性中间神经元的显著减少。具体地说，GABA能中间神经元功能下降可能是海马输出异常的原因。啮齿类学生在MAM模型（一种经验证的精神分裂症妊娠中断模型）中进行的研究表明，通过TTX失活抑制异常的腹侧海马活动，我们观察到多巴胺系统功能的恢复。在这里，我们将利用一种新的程序来恢复腹侧海马中间神经元的功能，从胚胎大鼠的内侧神经节隆起的GABA能神经元移植到腹侧海马的青春期后MAM治疗的大鼠。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，提供了一种新的治疗靶点。我们计划评估MGE细胞移植在MAM处理的大鼠中的作用，具体目的如下：1）确定GFP+ vHipp GABA能前体细胞移植对腹侧海马和多巴胺神经元活性的作用，以及2）确定GFP+ vHipp GABA能前体细胞移植是否将逆转与MAM处理的大鼠所见的阳性、阴性和认知缺陷相关的行为。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理学干预提供新的靶点。

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.