Impact of Pten mutations on brain growth and social behavioral development.

 描述（由申请人提供）：大脑过度生长与ASD的行为和认知症状之间的关系知之甚少。例如，PTEN是自闭症谱系障碍（ASD）和大头畸形的易感基因，其在整个发育和成年期的大脑中广泛表达。它还编码一个关键的调节途径-PI 3 K-Akt-mTOR-这是强烈牵连的ASD发病机制和治疗，以及基本控制细胞生长。目前，我们缺乏对胚系PTEN突变引起的大脑生长轨迹变化如何与ASD的行为和认知症状以及潜在神经回路组装相关的机械理解。我们的总体目标是通过利用PI 3 K-Akt-mTOR通路失调和大脑过度生长的小鼠模型来弥合我们知识中的这一差距。我们在这里提出的新假设是，Pten突变的一个影响是使与社会行为相关的关键细胞类型的正常生长模式去分化，从而使社会行为背后的下游连接和突触功能转向病理状态。我们推测腹侧被盖区的多巴胺能神经元是这种效应的候选细胞类型。我们建议开展这项工作的特点发展和成年Pten haploinsufficient小鼠的大脑生长轨迹和社会行为表型，通过检查是否遗传和药理学抑制5-HT 2cR在发展过程中，并在成年期可以扭转这些表型，并通过调查多巴胺能神经元是否可能是一种细胞类型相关的这些影响。这项研究将有助于我们了解自闭症的神经生物学，揭示Pten通过调节多巴胺能神经元中的5-HT 2cR影响大脑生长和社会行为发展的机制。这一贡献将是重要的，因为它将是一系列研究的第一步，这些研究有望导致新的药物遗传学方法，这些方法将允许在细胞类型生长水平上对特定ASD风险因素的社会行为缺陷进行回路水平的纠正。此外，该提议是创新的，因为它为自闭症、PI 3 K-Akt-mTOR通路和在特定G蛋白偶联受体（GPCR）-神经细胞类型相互作用水平上调节大脑生长的研究奠定了基础，这对社会行为很重要。随着这些策略变得可用，存在这样的前景，即可以基于他们已经暴露于的独特的一组风险因素，针对患有ASD的给定个体的症状合理地选择治疗方法。因此，我们可以预期，这项研究将导致ASD和其他神经精神疾病的治疗取得重要进展，这些疾病的特征是社会行为缺陷，大脑生长改变和/或PI 3 K-Akt-mTOR通路失调。此外，这一研究方向将提供更广泛的见解，以了解社会行为如何在大脑中特定细胞类型和回路的水平上发展，以及神经调节GPCR的调节如何有助于这一过程。

 DESCRIPTION (provided by applicant): The relationship between brain overgrowth and the behavioral and cognitive symptoms of ASD is poorly understood. For example, PTEN is a susceptibility gene for autism spectrum disorder (ASD) and macrocephaly that is broadly expressed in the brain throughout development and adulthood. It also encodes a key regulator of a pathway-PI3K-Akt-mTOR-that is strongly implicated in ASD pathogenesis and treatment, as well as basic control of cellular growth. At present, we lack a mechanistic understanding of how changes in the trajectory of brain growth caused by germline PTEN mutations relates to the behavioral and cognitive symptoms of ASD and the assembly of underlying neural circuitry. Our overall goal is to bridge this gap in our knowledge by making use of a mouse model of PI3K-Akt-mTOR pathway dysregulation and brain overgrowth. The novel hypothesis that we develop here is that one effect of Pten mutations is to desynchronize the normal pattern of growth in key cell types relevant for social behavior, thus diverting the downstream connectivity and synaptic function of circuitry underlying social behavior toward a pathological state. We speculate that dopaminergic neurons in the VTA are a candidate cell type for this effect. We propose to carry out this work by characterizing developing and adult Pten haploinsufficient mice for brain growth trajectory and social behavioral phenotypes, by examining whether genetic and pharmacological suppression of 5-HT2cR during development and in adulthood can reverse these phenotypes, and by investigating whether dopaminergic neurons may be a cell type relevant to these effects. The proposed research will contribute to our knowledge of the neurobiology of autism through uncovering a mechanism by which Pten influences brain growth and the development of social behavior via the regulation of 5-HT2cR in dopaminergic neurons. This contribution will be significant because it will be the first step in a line of research expected to lead to novel pharmacogenetic approaches that will allow for circuit-level corrections of social behavioral deficits specific to a given ASD risk factor at the level of cell type growth. Furthermore, this proposal is innovative because it grounds the study of autism, the PI3K-Akt-mTOR pathway and regulation of brain growth at the level of a specific G-protein coupled receptor (GPCR)-neural cell type interaction important for social behavior. As such strategies become available, there is the prospect that therapeutic approaches could be rationally selected for the symptoms of a given individual with ASD based on the unique set of risk factors they have been exposed to. Thus, we can expect that this research will lead to important advances in the treatment of ASD and other neuropsychiatric disorders that feature social behavioral deficits, altered brain growth and/or dysregulation of the PI3K-Akt-mTOR pathway. Furthermore, this line of investigation will provide broader insight into how social behavior develops at the level of specific cell types and circuits in the brain, and how the regulation of neuromodulatory GPCRs contributes to this process.