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Mechanisms of Synapse Remodeling of Cortical GABAergic Interneurons

皮质 GABA 能中间神经元突触重塑机制

基本信息

批准号：
9391408
负责人：
Chelsea Suzanne Sullivan
金额：
$ 0.14万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9391408
关键词：
Acute Address Adhesions Area Autistic Disorder Binding Biological Assay Bipolar Disorder Brain CSPG3 gene Cell Adhesion Molecules Cell surface Cognitive deficits Complex Data Development Disease Equilibrium Etiology Event Extracellular Domain Goals Growth Cones Image Immunoglobulins Inhibitory Synapse Interneurons Knockout Mice Ligands Link LoxP-flanked allele Medial Mediating Molecular Mus Mutant Strains Mice Myoepithelial cell NCAM1 gene Neural Cell Adhesion Molecules Neurites Neurodevelopmental Disorder Neurons Output Parvalbumins Play Prefrontal Cortex Presynaptic Receptors Process Property Protein Tyrosine Kinase Pyramidal Cells Receptor Protein-Tyrosine Kinases Regulation Reporter Research Role Schizophrenia Short-Term Memory Signal Transduction Slice Synapses Synaptic plasticity Testing conditional mutant experimental study hippocampal pyramidal neuron in vivo insight mouse development mouse model mutant nerve supply nervous system disorder neuropsychiatric disorder novel postnatal postsynaptic premature presynaptic prevent receptor synaptogenesis two-photon

项目摘要

Abstract Establishment of a proper balance of excitatory and inhibitory (E/I) connectivity is achieved during development of cortical networks and adjusted through synaptic plasticity, but there are fundamental gaps in our understanding of how this process is regulated. Without further characterization of developmental synapse remodeling, our understanding of neuropsychiatric disorders associated with GABAergic inhibitory connection disruption such as schizophrenia and autism is limited. The purpose of this research is to characterize molecular mechanisms that establish E/I balance in the prefrontal cortex, which may identify novel targets for treatment of disorders in which E/I balance is altered. The specific goal of this proposal is to define a mechanism for limiting inhibitory connections between GABAergic basket interneurons and pyramidal neurons. The central hypothesis of this proposal is that neural cell adhesion molecule NCAM and tyrosine kinase EphA3 form a presynaptic receptor complex for postsynaptic ephrinA5 to promote elimination of perisomatic synapses during early postnatal development of the prefrontal cortex (PFC). I also hypothesize that formation of perineuronal nets (PNNs) in later postnatal development of the PFC terminates NCAM/EphA3-mediated basket cell remodeling. To address these hypotheses, I will (1) characterize the importance of NCAM/EphA3 binding by using non-binding mutants in functional assays including receptor clustering, downstream EphA3 signaling, and growth cone collapse, (2) determine whether Neurocan competitively inhibits binding of NCAM/EphA3, (3) develop novel mouse models to conditionally delete NCAM in cortical neurons and assess perisomatic synapse remodeling using live two-photon imaging, and (4) test whether PNNs prevent remodeling of basket cells in brain slices. The findings of these studies are expected to be of great value to our understanding of novel molecular mechanisms of synapse remodeling of GABAergic interneurons in postnatal PFC and could provide insight into the etiology of neurological disorders involving E/I balance disruption.

摘要