Perisomatic Inhibitory Network Dysfunction in Neurological Disease

神经系统疾病中的体周抑制网络功能障碍

基本信息

批准号：
8238495
负责人：
Vijayalakshmi Santhakumar
金额：
$ 32.46万
依托单位：
UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8238495
关键词：
Address Adopted Affect Age Antiepileptic Agents Behavior Buffers Characteristics Chemicals Coupling Data Development Diagnosis Disease Drug Delivery Systems Drug resistance Epilepsy Epileptogenesis Feedback GABA Receptor GABA transporter Gap Junctions Genetic Goals Heart Hippocampus (Brain)Interneurons Kinetics Lead Mainstreaming Measures Mus Myoepithelial cell Nature Neurons Parvalbumins Patients Pattern Physiological Pilocarpine Quality of life Rattus Resistance Risk Rodent Seizures Slice Status Epilepticus Synapses Syndrome Temporal Lobe Epilepsy Testing United States alternative treatment computer studies dentate gyrus extracellular gamma-Aminobutyric Acid granule cell inhibitory neuron large scale simulation model development nervous system disorder network dysfunction network models novel research study simulation

Address Adopted Affect Age Antiepileptic Agents Behavior Buffers Characteristics Chemicals Coupling Data Development Diagnosis Disease Drug Delivery Systems Drug resistance Epilepsy Epileptogenesis Feedback GABA Receptor GABA transporter Gap Junctions Genetic Goals Heart Hippocampus (Brain)Interneurons Kinetics Lead Mainstreaming Measures Mus Myoepithelial cell Nature Neurons Parvalbumins Patients Pattern Physiological Pilocarpine Quality of life Rattus Resistance Risk Rodent Seizures Slice Status Epilepticus Synapses Syndrome Temporal Lobe Epilepsy Testing United States alternative treatment computer studies dentate gyrus extracellular gamma-Aminobutyric Acid granule cell inhibitory neuron large scale simulation model development nervous system disorder network dysfunction network models novel research study simulation

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项目摘要

DESCRIPTION (provided by applicant): An estimated 200,000 new cases of epilepsy are diagnosed each year in the United States. Temporal lobe epilepsy, the most common epileptic syndrome, often develops following early unprovoked seizures and is particularly resistant to mainstream antiepileptic drugs. The hippocampal dentate gyrus is at the heart of the characteristic structural and functional changes that underlie temporal lobe epilepsy. A network of perisomatically projecting GABAergic interneurons regulates the excitability of dentate projection neurons, the granule cells. Activity and synchrony of inhibitory networks are governed by a combination of gap junctional and GABAergic chemical connections. However, whether GABAergic inhibition and electrical coupling among the perisomatic interneurons are modified during development of epilepsy and underlie the instability in network activity in epilepsy is yet to be examined. Additionally, dynamic changes in inhibitory and electrical coupling among interneurons are likely to determine the duration and spread of seizures. Understanding how activity patterns in the perisomatic inhibitory network are altered following status epilepticus and dynamically regulated during seizures will help evaluate whether pharmacological manipulation of gap junctions and GABA receptors would be effective in treating epilepsy. The hypothesis of this proposal is that status epilepticus (SE) alters non-synaptic and synaptic coupling between fast-spiking perisomatic dentate interneurons resulting in enhanced mutual inhibition which compromises feedback inhibition of projection neurons. It is further proposed that modulation of inhibitory currents and electrical coupling by pH changes that accompany neuronal activity undermine perisomatic inhibition during neuronal activity enhancing dentate excitability and contributing to epileptogenesis. The study will use pilocarpine induced status epilepticus to model development of acquired epilepsy, and a combination of anatomical, physiological and computational approaches to address the following specific questions. Aim 1 will identify the presence of tonic GABA currents in fast-spiking basket cells and examine whether post-status enhancement of tonic GABA currents compromise perisomatic inhibition of granule cells. Aim 2 will identify post-status changes in synaptic and electrical coupling among basket cells and their effects on dentate network excitability and synchrony. Aim 3 will test whether activity-dependent modulation of basket cell synaptic and non-synaptic coupling by acidic pH shifts accompanying neuronal activity undermines inhibition and contributes to epileptogenesis after status epilepticus. It is anticipated that the study will identify fundamental mechanisms underlying dynamical instability of dentate network activity in acquired epilepsy. PUBLIC HEALTH RELEVANCE: Acquired temporal lobe epilepsy is a disorder affecting over 1.5 million patients and is associated with long term decrease in quality of life. The experiments proposed in this study will determine if dynamic decreases in inhibition during seizures contributes to prolonged neuronal activity and development of epilepsy. It is expected that understanding the changes in inhibitory circuit function in epilepsy will lead to novel alternatives to manage patients with early unprovoked seizures and reduce the risk for developing epilepsy.