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GABAergic contributions to neural circuit deficits in schizophrenia

GABAergic 对精神分裂症神经回路缺陷的贡献

基本信息

批准号：
8612465
负责人：
JESSICA A CARDIN
金额：
$ 41.63万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8612465
关键词：
Adolescent Affect Animals Behavioral Biological Neural Networks Brain Candidate Disease Gene Cells Cerebral cortex Cognition Cognitive Complex Data Development Disease Disinhibition Electrophysiology (science)Elements Embryo ErbB4 Receptor Protein Tyrosine Kinase ErbB4 gene Etiology Exhibits Foundations Frequencies Functional disorder Generations Genetic Genetic Models Goals Human Hyperactive behavior Impaired cognition Impairment In Vitro Inhibitory Synapse Interneuron function Interneurons Knowledge Lead Link Measurement Membrane Memory Mental disorders Methods Modeling Mus Neuregulin 1 Neurons Neurophysiology - biologic function Parvalbumins Patients Perception Play Population Process Pyramidal Cells Relative (related person)Role Schizophrenia Sensory Shapes Signal Pathway Signal Transduction Somatostatin Synapses System Testing Therapeutic Time Visual Cortex Visual Perception Work area striata awake base brain cell cell type cellular targeting excitatory neuron extracellular gamma-Aminobutyric Acid in vivo inhibitory neuron innovation insight migration mouse model neural circuit novel novel therapeutics operation optogenetics postnatal postsynaptic prenatal prepulse inhibition public health relevance receptor binding research study reuptake screening sensory integration synaptic inhibition synaptogenesis visual process visual processing

项目摘要

DESCRIPTION (provided by applicant): Genetic factors appear to play a major role in the etiology of schizophrenia, a devastating mental illness that affects up to 1% of the worldwide population. Recent evidence suggests disruption of GABAergic inhibitory interneurons in the brain as a strong candidate underlying mechanism. Our long-term goal is therefore to understand the role of inhibitory dysfunction in the pathophysiology of this psychiatric disease. Identifying the mechanisms by which inhibitory dysregulation during development leads to perturbation of cortical function will give insight into the neurodevelopmental cellular mechanisms underlying schizophrenia and may provide new cellular targets for therapeutic strategies. Human screening studies have identified Neuregulin-1 (Nrg-1), an extracellular signaling factor, and its membrane-bound receptor ERBB4 (ErbB4), as strong candidate genes for schizophrenia. Most evidence indicates that ErbB4 protein is expressed predominantly in GABAergic cells throughout the brain. Global disruptions of ErbB4 result in decreased GABA release in the cerebral cortex, and mice lacking Nrg-1 or ErbB4 exhibit key behavioral deficits associated with schizophrenia. The ErbB4 model of schizophrenia is thus an ideal system in which to examine the cell type-specific role of inhibitory interneuron dysregulation in cortical network perturbation in this complex disorder. A major issue in using genetic mouse models to study psychiatric disease has been that many studies focus on single cells or synapses in vitro. In contrast, the cognitive and perceptual processes disrupted in schizophrenia rely on large-scale neural network interactions in the intact brain. We will therefore examine neural function in vivo in primary visual cortex circuits in the ErbB4 deletion model of schizophrenia. Synaptic and circuit function in the healthy visual cortex and the contribution of these circuits to visual processing are well characterized, providing a critical framework in which to interpret disease-related alterations in cellular and network function. Furthermore, schizophrenic patients exhibit specific deficits in basic visual processing and perception that rely on primary visual cortex function. We will use a combination of intra- and extracellular recordings and cell type-specific optogenetic manipulations to test the impact of ErbB4 deletion on the function of inhibitory interneurons in cortical networks in vivo in awake behaving animals. Using measurements of key aspects of cortical circuit function at the synaptic and circuit levels, we will assess the rol of ErbB4 signaling in interactions between inhibitory and excitatory neurons. We will further use targeted genetic approaches to examine the developmental role of this signaling pathway in the survival and maturation of specific populations of GABAergic cells. These studies will reveal fundamental mechanisms underlying circuit dysfunction in this genetic model of schizophrenia and lead to a more complete understanding of the cell type-specific role of GABAergic dysfunction in psychiatric disease. Because the cellular and circuit interactions identified in thi work are core elements of neural function, our results will be applicable to systems throughout the brain.