Thalamocortical circuit defects in developmental brain disorders

发育性脑疾病中的丘脑皮质回路缺陷

基本信息

批准号：
9045102
负责人：
Reha S Erzurumlu
金额：
$ 49.05万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
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：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9045102
关键词：
Adult Affect Alleles Animals Anxiety Autonomic Dysfunction Behavior Behavioral Biochemical Biological Biological Assay Biological Process Birds Brain Brain Diseases Brain Stem Brain imaging Brain region Cells Child Childhood Cognitive Communication DNA Sequence Alteration Data Defect Development Dyes Electrophysiology (science)Equilibrium Etiology Eye Face Flavoring Functional Imaging Functional Magnetic Resonance Imaging Functional disorder GABA Receptor Gene Deletion Gene Expression Genes Genetic Genome Glutamates Hand Hepatocyte Growth Factor Human Immediate-Early Genes Impairment Individual Intellectual functioning disability Knockout Mice Ligands Light Link MET gene Magnetic Resonance Spectroscopy Methyl-CpG-Binding Protein 2 Molecular Movement Mus Mutation Neocortex Neurodevelopmental Disorder Neurons Neurotransmitters Pathway interactions Pattern Perception Phenotype Physiological Physiology Preparation Property Prosencephalon Receptor Protein-Tyrosine Kinases Relative (related person)Rett Syndrome Risk Factors Seizures Sensory Sensory Process Signal Transduction Slice Stereotyping Symptoms Synapses Synaptic Transmission Synaptic plasticity System Testing Thalamic structure Time Transcription Coactivator Transcription Repressor/Corepressor Trigeminal Nuclei Trigeminal System Vibrissae X Chromosome autism spectrum disorder barrel cortex base behavior test density developmental disease excitatory neuron experience gene function genetic manipulation in vivo information processing loss of function male meetings migration motor disorder mouse model neocortical neurogenesis neurotransmission overexpression postnatal presynaptic public health relevance receptor research study sensory mechanism somatosensory synaptic function therapeutic development voltage voltage clamp

项目摘要

DESCRIPTION (provided by applicant): There is increasing evidence, implicating disruption of excitatory and inhibitory neurotransmission in the etiology of Autism Spectrum Disorders (ASD) and Rett Syndrome (RTT). Specific genetic effects are associated with these developmental disorders. MET receptor and it ligand hepatocyte growth factor (HGF) and both are expressed in the developing brain. The human gene MET, which encodes MET receptor tyrosine kinase has been identified as a prominent risk factor for ASD. RTT is a neurodevelopmental disorder caused by mutations in the MECP2 gene. Met and Mecp2 loss-of-function mouse models provide invaluable opportunities in understanding morphological and physiological changes in various brain regions, and they allow for development of therapeutic strategies. Both ASD and RTT affected children display distinct somatosensory behavioral proclivities suggesting specific defects in somatosensory information processing. We focus on the somatosensory thalamocortical circuit physiology and in vivo functional analyses in development, using region-specific genetic loss of function mouse models to uncover basic scientific mechanisms of thalamocortical circuitry defects following genetic disruption of these two genes associated with ASD and RTT. Our preliminary results in the Bird mouse model of MeCP2 deficiency indicate that the balance of excitation and inhibition in Layer 4 excitatory neurons of barrel cortex is biased toward inhibition. In contrast when Met signaling is disrupted in cortical excitatory neurons, heterozygous mice show loss of inhibition. We focus on the mouse primary somatosensory (whisker "barrel") cortex because of its patterned organization and well-characterized development and plasticity. We combine mouse genetics with electrophysiological, functional imaging, biochemical, and behavioral analyses to understand the cellular mechanisms and consequences of thalamocortical circuitry defects following these specific genetic disruptions.

描述（由适用提供）：在自闭症谱系障碍（ASD）和RETT综合征（RTT）的病因中，有越来越多的证据，暗示兴奋和抑制性神经传递。具体的遗传效应与这些发育障碍有关。 MET受体及其配体肝细胞生长因子（HGF），两者在发育中的大脑中表达。编码MET受体酪氨酸激酶的人类基因已被确定为ASD的突出危险因素。 RTT是由MECP2基因突变引起的神经发育障碍。 MET和MECP2功能丧失的小鼠模型为理解各个大脑区域的形态和身体变化提供了宝贵的机会，它们允许发展理论策略。 ASD和RTT影响的儿童都表现出不同的体感行为倾向，这表明体感信息处理中的特定缺陷。我们使用官能小鼠模型的区域特异性遗传损失来探讨这两个与ASD和RTT相关的两个基因的遗传破坏后，使用区域特异性的遗传小鼠模型的遗传遗传损失，以发现丘脑皮质电路缺陷的基本科学机制，从而发现了发育中的体体性丘脑皮层生理学和体内功能分析。我们在MECP2缺乏症的鸟小鼠模型中的初步结果表明，枪管皮层第4层兴奋性神经元中兴奋和抑制的平衡偏向抑制。相比之下，当MET信号传导破坏皮质兴奋性神经元时，杂合小鼠显示出抑制作用的损失。我们专注于小鼠原发性体感（晶须“枪管”）皮质，因为其具有图案化的组织以及表征良好的发育和可塑性。我们将小鼠遗传学与电生理学，功能成像，生化和行为分析相结合，以了解这些特定遗传破坏后丘脑皮质回路缺陷的细胞机制和后果。