Sex-specific mechanisms of cortical circuit dysfunction in a mouse ASD model

小鼠 ASD 模型中皮质回路功能障碍的性别特异性机制

• 批准号: 10052919
• 负责人: KIMBERLY M. HUBER
• 金额: $ 209.63万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10052919
• 关键词: 16p11.2; Acute; Address; Affect; Automobile Driving; Behavior; Behavior Disorders; Behavioral; Brain; Brain region; Cells; Child; Clinical Trials; Cognition; Collaborations; Complex; Coupled; Data; Diagnosis; Disease; Disease model; Dissociation; Drug Addiction; Electroencephalography; Embryo; Equilibrium; Estradiol; Estrogen Receptor alpha; Estrogens; Exhibits; FMR1; Family; Female; Fragile X Syndrome; Frequencies; Functional disorder; Gender; Genes; Genetic; Hippocampus (Brain); Human; Hyperactive behavior; Knock-out; Lead; Lesion; Link; Mediating; Membrane; Modeling; Molecular; Mus; Neurons; PTEN gene; Pathway interactions; Phenotype; Physiology; Property; Regulation; Research; Rest; Rett Syndrome; Role; Scaffolding Protein; Sensory; Sex Differences; Signal Transduction; Symptoms; Synapses; Testing; Tuberous Sclerosis; Women' s Role; Work; autism spectrum disorder; brain dysfunction; feeding; gene function; in vivo; male; metabotropic glutamate receptor type 1; mouse model; neocortical; neurophysiology; patch clamp; postnatal; postsynaptic; reproductive; response; sex; sound

Although ASD is more diagnosed in males, the behavioral manifestations of ASD, as well as the neuroanatomical changes and brain dysfunction associated with ASD, differ between males and females. There is little known of how ASD genes impact the female brain. Estrogen, acting through membrane bound estrogen receptor α (ERα), interacts with and activates Gq-coupled Group 1 mGluRs, mGluR1 and mGluR5, selectively in female neurons in diverse brain regions to regulate signaling, neurophysiology, and behavior. Altered functioning of mGluRs, primarily mGluR5, is strongly implicated in the pathophysiology of ASD mouse models, most notably Fragile X Syndrome, but many others, and mGluR5 antagonists are in clinical trials of FXS children. We were the first to discover hyperactivity of mGluR5 function in the FXS mouse model, Fmr1 KO, and show this results from an abnormal mGluR5 complex; mGluR5 is dissociated from its postsynaptic scaffolding protein, Homer, which, in turn, leads to constitutive mGluR5 activity, abnormal signaling to downstream effectors and disease relevant phenotypes, such as circuit hyperexcitability. Despite the evidence for mGluR5 in ASD pathophysiology, the known sex-dependent regulation of mGluR1/5 by estrogen, little is known of how ASD-linked genes interact with estrogen to affect mGluR1/5 function and the consequences on ASD-relevant neurophysiology and behavior. We have discovered a sex-specific, mGluR5 -dependent dysfunction of sensory neocortical circuits in a mouse model of ASD that results from deletion of Pten (Phosphatase and tensin homolog deleted on chromosome 10), a suppressor of the PI3K/mTORC1 pathway. Specifically, we observe hyperexcitable neocortical circuit oscillations, termed UP states, in females of two distinct PTEN deletion models; an embryonic, knockout of Pten in hippocampus and layer 5 neocortical neurons, and a germline Pten heterozygous mouse (Pten-het), which is a genetically valid model for Pten-related ASD in humans. Hyperexcitable UP states in female Pten models are corrected by acute antagonism of mGluR5 or ERα, indicative of hyperactive mGluR5- ERα signaling. A candidate molecular substrate for enhanced mGluR5-ERα activity is the observed increase in mGluR5-ERα, and decreased mGluR5-Homer, complexes in female Pten-het cortex. We hypothesize that an imbalance in mGluR5 interactions with ERa and Homer in Pten deleted female neurons results in enhanced mGluR5-signaling in response to estrogen, acting on ERα, as well as constitutively active mGluR5 which leads to hyperexcitable cortical oscillations and ASD-relevant behaviors. We propose the following aims to test this hypothesis: Aim 1: Determine the sex-dependent interactions of Pten and ERα in cortical circuit dysfunction and mGluR5 complex regulation. Aim 2: Examine the sex-specific effects of mGluR5 and ERα on intrinsic and synaptic properties of Pten-deleted layer 5 neurons. Aim 3: Determine the sex-specific, mGluR5- and ERα-dependent in vivo cortical oscillations with EEG in Pten deletion models. Aim 4. Determine the role of female-specific, Pten-dependent cortical circuit hyperexcitability in ASD-relevant behaviors.

尽管ASD在男性中被诊断出更多，但ASD的行为表现以及神经解剖学 与ASD相关的变化和大脑功能障碍，男性和女性之间的不同。鲜为人知 ASD基因如何影响女性大脑。雌激素，通过膜结合的雌激素受体α（ERα）作用， 在女性神经元中有选择地与GQ耦合1 mglurs Mglur1和mglur5相互作用并激活MGLUR1和MGLUR5 在潜水大脑区域中，调节信号传导，神经生理学和行为。 mglurs的功能改变， 主要mglur5与ASD小鼠模型的病理生理非常重要，最著名的是脆弱的x 综合征，但许多其他人和MGLUR5拮抗剂正在FXS儿童的临床试验中。我们是第一个 在FXS小鼠模型FMR1 KO中发现MGLUR5功能的多动症，并显示了这一点 MGLUR5复合物异常； mglur5与其突触后脚手架蛋白质荷马分离，该蛋白在 转弯，导致组成型MGLUR5活性，异常信号传导到下游效应和疾病相关 表型，例如电路过度兴奋性。尽管有ASD病理生理学中MGLUR5的证据，但 雌激素对MGLUR1/5的性别依赖性调节，鲜为人知的是ASD连接基因如何与 雌激素会影响MGLUR1/5功能以及对与ASD相关的神经生理学和行为的后果。 我们已经发现了一种性别特异性的mglur5依赖性功能障碍在一个中的感觉新皮层电路 由PTEN删除（磷酸酶和Tensin同源物在上删除的）ASD的小鼠模型 染色体10），PI3K/MTORC1途径的抑制剂。具体来说，我们观察到过度可观 新皮层电路振荡，称为状态，在两个不同的PTEN缺失模型的女性中；胚胎， 海马和5层新皮质神经元中的PTEN敲除，以及种系PTEN杂合小鼠 （PTEN-HET），这是人类与PTEN相关的ASD的一般有效模型。在 女性PTEN模型通过mglur5或erα的急性拮抗作用校正，表明MGLUR5-- ERα信号传导。候选分子底物用于增强MGLUR5-ERα活性是观察到的增加 MGlur5-ERα和改善的MGLUR5-HOMER，雌性PTEN-HET皮层中的复合物。我们假设 MGLUR5与ERA的不平衡和PTEN删除的雌性神经元中的荷马相互作用导致 响应于雌激素的ERα上以及组成性活跃的雌激素响应增强的MGLUR5信号 MGLUR5导致过度可见的皮质振荡和与ASD相关的行为。我们建议 以下目的是检验此假设：目标1：确定PTEN和ERα在 皮质回路功能障碍和MGLUR5复合调节。目标2：检查mglur5的性别特定效果 ERα在5层神经元的固有和突触特性上。 AIM 3：确定性别特定， MGlUR5-和ERα依赖性在PTEN缺失模型中用脑电图的体内皮质振荡。目标4。确定 女性特异性，依赖PTEN依赖性皮质回路在与ASD相关的行为中的作用。

项目成果

Editorial: Recent advances in mechanisms and therapeutics for Fragile X Syndrome and autism.

• DOI: 10.3389/fnins.2023.1187799
• 发表时间: 2023
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Molinaro, Gemma;Huber, Kimberly M. M.;McCullagh, Elizabeth A. A.;Thomson, Sophie R. R.
• 通讯作者: Thomson, Sophie R. R.

Increased glycine contributes to synaptic dysfunction and early mortality in Nprl2 seizure model.

• DOI: 10.1016/j.isci.2022.104334
• 发表时间: 2022-05-20
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Dentel, Brianne;Angeles-Perez, Lidiette;Ren, Chongyu;Jakkamsetti, Vikram;Holley, Andrew J.;Caballero, Daniel;Oh, Emily;Gibson, Jay;Pascual, Juan M.;Huber, Kimberly M.;Tu, Benjamin P.;Tsai, Peter T.
• 通讯作者: Tsai, Peter T.