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

Pten 突变对大脑生长和社会行为发展的影响。

基本信息

批准号：
9119091
负责人：
Damon Theron Page
金额：
$ 48万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9119091
关键词：
Adolescent Adult Animal Model Animals Autistic Disorder Behavior Behavior Control Behavioral Behavioral Assay Behavioral Symptoms Biological Biological Assay Biology Brain Brain Mass Chronic Cognitive deficits Development Diagnosis Disease Dopamine Embryonic Development FMR1 FRAP1 gene Funding G-Protein-Coupled Receptors Genes Genetic Genetic Heterogeneity Goals Growth Growth and Development function Head Health Heterogeneity Hyperplasia Hypertrophy Individual Investigation Knock-out Knowledge Laboratories Lead Link Macrocephaly Marble Measures Modeling Modification Molecular Target Mus Mutation NF1 gene Neurobehavioral Manifestations Neurobiology Neurons PTEN gene Pathogenesis Pathway interactions Pattern Pharmacogenetics Phenotype Population Process Regulation Reporting Research Risk Factors Serotonin Signal Transduction Social Behavior Specific qualifier value Susceptibility Gene Symptoms TSC1/2 gene Testing Therapeutic Time Wild Type Mouse Work autism spectrum disorder base behavior measurement brain overgrowth cell growth cell type cellular targeting design disorder risk dopaminergic neuron genetic risk factor innovation insight mouse model neural circuit neuropsychiatric disorder neuroregulation novel ranpirnase repetitive behavior research study risk variant serotonin receptor sex social stem synaptic function

项目摘要

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.