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

 描述(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尚不清楚。例如，PTEN是自闭症谱系障碍(ASD)和巨头症的易感基因，在整个发育和成年过程中在大脑中广泛表达。它还编码一个关键的调控通路-PI3K-Akt-mTOR-与ASD的发病和治疗以及细胞生长的基本控制密切相关。目前，对于胚系PTEN突变引起的脑生长轨迹的改变与ASD的行为和认知症状以及潜在神经回路的组装之间的关系，我们缺乏机械性的理解。我们的总体目标是通过利用PI3K-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失去同步，从而将潜在社会行为的回路的下游连接和突触功能转移到一种病理状态。我们推测，VTA中的多巴胺能神经元是这种效应的候选细胞类型。我们建议通过表征发育中和成年的Pten单倍体缺陷小鼠的脑生长轨迹和社会行为表型，检查在发育和成年期对5-HT2cR的遗传和药物抑制是否可以逆转这些表型，并通过调查多巴胺能神经元是否可能是与这些影响相关的一种细胞类型，来开展这项工作。这项拟议的研究将通过揭示Pten通过调节多巴胺能神经元中的5-HT2cR影响大脑发育和社会行为发展的机制，有助于我们了解自闭症的神经生物学。这一贡献将是重要的，因为它将是一系列研究的第一步，预计将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风险因素的特定社会行为缺陷进行电路水平的纠正。此外，这一建议是创新的，因为它为自闭症、PI3K-Akt-mTOR通路的研究以及在特定G蛋白偶联受体(GPCR)-神经细胞类型相互作用的水平上调节大脑生长奠定了基础，这种相互作用对社会行为非常重要。随着这些策略的出现，有可能根据ASD患者暴露于独特的风险因素集，针对特定ASD患者的症状合理选择治疗方法。因此，我们可以预期，这项研究将在ASD和其他神经精神疾病的治疗方面取得重要进展，这些疾病的特征是社会行为缺陷、脑生长改变和/或PI3K-Akt-mTOR通路调节失调。此外，这一系列研究将提供更广泛的洞察力，了解社会行为是如何在大脑中特定细胞类型和回路的水平上发展的，以及神经调节GPCRs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.