权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Thalamocortical network dysfunction in a novel genetic model of GRIN2D developmental and epileptic encephalopathy

GRIN2D 发育性和癫痫性脑病新型遗传模型中的丘脑皮质网络功能障碍

基本信息

批准号：
10195508
负责人：
WAYNE N. FRANKEL
金额：
$ 44.55万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10195508
关键词：
Absence Epilepsy Acute Adult Affect Animal Genetics Animal Model Animals Attention Awareness Biological Assay Brain Brain region Cell Nucleus Cell physiology Cells Cerebral cortex Childhood Clinical Cognition Cognitive Collaborations Collection Data Development Developmental Delay Disorders Docking Electrophysiology (science)Epilepsy Epileptogenesis Equilibrium Etiology Evaluation Future Generations Genes Genetic Genetic Models Glutamates Glycine Goals Hippocampus (Brain)Impaired cognition Impairment In Vitro Investigation Kinetics Laboratories Maintenance Measures Mediating Mediator of activation protein Membrane Proteins Methods Modeling Motor Motor Seizures Mus Mutation Mutation Analysis N-Methyl-D-Aspartate Receptors N-Methylaspartate Neurologic Symptoms Neurons Pathogenicity Pathologic Pathology Patients Pharmacology Phenotype Physiologic pulse Physiology Population Predisposition Preparation Property Proteins Receptor Activation Regulation Reproducibility Research Rodent Model Seizures Shapes Signal Transduction Site Sleep Slice Source Structure Synapses System Thalamic structure Therapeutic Time Whole-Cell Recordings Work base behavioral impairment biophysical analysis cell cortex cognitive enhancement density design epileptic encephalopathies excitotoxicity experience experimental study functional disability gain of function mutation gene therapy improved in vivo inhibitory neuron innovation insight mouse model network dysfunction neural circuit neuropsychiatric symptom neurotransmission novel patch clamp postnatal development preservation programs protein complex response sleep regulation somatosensory success synaptic function synaptic inhibition synaptogenesis targeted treatment voltage clamp

项目摘要

PROJECT SUMMARY Developmental and epileptic encephalopathy (DEE) is a collection of severe childhood seizure disorders, with a significant and diverse genetic component. DEE patients usually experience a significant seizure burden and suffer from cognitive and developmental impairments, as well as sleep and motor disturbances. The 50 or more genes harboring DEE-causing mutations include the “GRIN” genes, which encode components of membrane protein complexes that are important for electrochemical signaling between neurons. Mutations in the GRIN2D subunit cause particularly severe and intractable DEE. We recently developed a mouse model of GRIN2D carrying a mutation that has recurred several times in GRIN2D DEE patients. These mice have very robust epileptic features, including both convulsive seizures and non-convulsive seizures known to be regulated by signaling between the cerebral cortex and the thalamus (i.e. thalamocortical network). This thalamocortical network is also associated with regulation of sleep, awareness, and the activity of many other brain regions. In preliminary findings, we also noticed that the protein product of Grin2D is expressed in excitatory and inhibitory cells of the cortex, while it is enriched in the inhibitory cells of the thalamus. Additionally, the primary sites of neuronal signaling – the synapse – have unusual structural features in the cortex, suggesting that they do not develop normally. Altogether, these preliminary data motivate an examination of how mutation in Grin2D alters the function of the cortex and thalamus. In this pilot program, we will apply electrophysiological approaches to measure the function of synapses in the GRIN2D DEE model to determine if structural changes correspond to functional impairments. We will also identify the neuronal connections that are most severely affected within the thalamocortical network in GRIN2D DEE. Aim1 will use slice electrophysiology methods to examine population-level responses within the cortex and thalamus to look for susceptibility of these regions to generate seizure-like activity. We will also adapt innovative approaches to dissect the component parts of the response in the cortex, which will allow us to efficiently pinpoint amongst the many connections in the cortex, which are most likely altered by the Grin2D mutation. These network-level effects will be further explored in Aim2 using intracellular whole-cell patch clamp recordings of synaptic currents. Aim2 will assess two distinct modes of GRIN2D signaling, synaptic and tonic, which are associated with different cellular consequences and are likely involved in the GRIN2D DEE pathogenic mechanism. Together these experiments will determine the consequence of the GRIN2D DEE mutation on the activity of neural circuits, which are implicated in the generation of seizures in these animals, and will determine, at the cellular level, the underlying mechanism of epileptogenesis. This study is an important first step for determining how GRIN2D shapes the development and maintenance of thalamocortical circuits (under normal conditions and in a DEE model), information which will guide future efforts to develop targeted corrective therapeutics.

项目总结