Imaging PTEN-induced changes in adult cortical structure and function in vivo

对 PTEN 诱导的成人皮质结构和功能的体内变化进行成像

基本信息

批准号：
8211003
负责人：
Joshua Trachtenberg
金额：
$ 30.02万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8211003
关键词：
1-Phosphatidylinositol 3-Kinase Action Potentials Adult Age Anxiety Apical Architecture Area Autistic Disorder Behavior Birth Cells Characteristics Child Chronic Data Set Dendrites Dendritic Cells Dendritic Spines Development Electric Capacitance Excision Exhibits Frequencies Gene Deletion Genes Genetic Goals Growth Human Hyperactive behavior Image Impairment Injection of therapeutic agent Interneurons Knock-out Knockout Mice Laser Scanning Microscopy Lead Learning Macrocephaly Measurement Measures Mediating Membrane Mental Retardation Mitotic Monozygotic Twinning Monozygotic twins Mus Mutation Neurodevelopmental Disorder Neurofibromatoses Neurons Oncogenes Oregon Output PTEN gene Pathway interactions Phosphoric Monoester Hydrolases Photic Stimulation Photons Physiology Population Predisposition Property Research Resistance Rest Role Sensory Physiology Sensory Process Shapes Signal Pathway Sirolimus Social Interaction Structure Syndrome TSC1/2 gene Testing Therapeutic Training Trees Tuberous Sclerosis Twin Multiple Birth Visual Cortex Visual Motion Width area striata autism spectrum disorder base calcium indicator cell type experience hippocampal pyramidal neuron human FRAP1 protein in vivo information processing mTOR Inhibitor neural circuit patch clamp postnatal preference programs public health relevance receptive field relating to nervous system research study response social social communication tensin

项目摘要

DESCRIPTION (provided by applicant): Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction and communication. Rates of autism have exploded over the past decade and it is now estimated that 1 out of every 166 children exhibit some form of autism. The neuropathological cause of autism remains elusive, though a strong genetic contribution is evident from the 60%-92% concordance between monozygotic twins versus 0-10% in dizogtic twins. Research in human populations indicates that the number of loci associated with autism exceeds 15. Of specific relevance to this proposal is the phosphatase and tensin homologe (Pten). This oncogene regulates the growth of post-mitotic neurons. The PTEN signaling pathway is emerging as one of two major pathways that regulate the susceptibility to autism spectrum disorders. Mice with a cortical Pten deletion exhibit many of the characteristics associated with autism, including macrocephaly, deficits in social interactions, impaired social learning, hyperactivity, and increased anxiety-like behavior. Many of these deficits are reversible with chronic treatment of the mTOR inhibitor, rapamycin. In this proposal, we employ mice in which the Pten gene is deleted specifically from the cortex by CRE-mediated excision beginning some 6-8 weeks after birth. We recently demonstrated that cortical layer 2/3 pyramidal neurons experience a unique growth of their apical dendrites following PTEN deletion. This growth expands the apical dendritic tree by upwards of 1mm and adds hundreds of new dendritic spines. Our goal is to fully characterize any changes in basic physiology and sensory information processing in these growing neurons. To this end we use 2-photon laser scanning microscopy to guide the placement of in vivo whole cell patch recordings from growing neurons in the mouse primary visual cortex. We also use 2-photon imaging to image network activity in the cortex of knockout and wildtype mice. Results from these studies may provide targets for the development of rationally based therapeutics for autism spectrum disorders. PUBLIC HEALTH RELEVANCE: The PTEN signaling pathway is emerging as one of two major pathways that regulate the susceptibility to autism spectrum disorders. We earlier characterized robust changes in dendritic structure in conditional knockout mice. Here we measure changes in physiology and sensory processing in these growing neurons using in vivo whole cell patch recordings and 2-photon in vivo imaging of network activity.

描述（由申请人提供）：自闭症是一种严重的神经发育障碍，其特征是社交互动和沟通障碍。过去十年中，自闭症发病率呈爆炸性增长，据估计，每 166 名儿童中就有 1 人患有某种形式的自闭症。自闭症的神经病理学原因仍然难以捉摸，尽管同卵双胞胎之间的一致性为 60%-92%，而异卵双胞胎的一致性为 0-10%，这显然有很强的遗传因素。对人群的研究表明，与自闭症相关的基因座数量超过 15 个。与该提议特别相关的是磷酸酶和张力蛋白同源物 (Pten)。该癌基因调节有丝分裂后神经元的生长。 PTEN 信号通路正在成为调节自闭症谱系障碍易感性的两条主要通路之一。皮质 Pten 缺失的小鼠表现出许多与自闭症相关的特征，包括大头畸形、社交互动缺陷、社交学习受损、多动和焦虑样行为增加。其中许多缺陷可以通过 mTOR 抑制剂雷帕霉素的长期治疗来逆转。在这个提议中，我们使用了小鼠，其中 Pten 基因在出生后约 6-8 周开始通过 CRE 介导的切除从皮层中特异性删除。我们最近证明，在 PTEN 缺失后，皮质层 2/3 锥体神经元的顶端树突经历了独特的生长。这种生长使顶端树突树扩大了 1 毫米以上，并增加了数百个新的树突棘。我们的目标是充分表征这些生长中的神经元的基本生理学和感觉信息处理的任何变化。为此，我们使用 2 光子激光扫描显微镜来指导小鼠初级视觉皮层中生长神经元的体内全细胞贴片记录的放置。我们还使用 2 光子成像对基因敲除小鼠和野生型小鼠的皮质网络活动进行成像。这些研究的结果可能为开发自闭症谱系障碍的合理疗法提供目标。公共健康相关性：PTEN 信号通路正在成为调节自闭症谱系障碍易感性的两条主要通路之一。我们之前描述了条件敲除小鼠树突结构的剧烈变化。在这里，我们使用体内全细胞斑块记录和网络活动的 2 光子体内成像来测量这些生长中的神经元的生理和感觉处理的变化。