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Hippocampal astrocytic Kir4.1 channel function in Type 2 diabetic mice: impact on neuronal hyperexcitability

2型糖尿病小鼠海马星形胶质细胞Kir4.1通道功能：对神经元过度兴奋的影响

基本信息

批准号：
10896699
负责人：
Miguel P Mendez
金额：
$ 6.72万
依托单位：
UNIVERSITY OF PUERTO RICO AT AGUADILLA
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：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10896699
关键词：
4-Aminopyridine Address Adult Affect Area Astrocytes Barium Biological Brain Buffers Cells Central Nervous System Communication Communities Data Dependovirus Diabetes Mellitus Diabetic mouse Diagnosis Disease Down-Regulation Electrophysiology (science)Epilepsy Equilibrium Event Female Functional disorder Genetic Glucose Goals Hippocampus Human Hyperglycemia Impairment Incidence Ions Knowledge Link Measures Medical Membrane Membrane Potentials Messenger RNA Molecular Morbidity - disease rate Mus Mutation Neurologic Neurons Non-Insulin-Dependent Diabetes Mellitus Nutrient Phenotype Population Potassium Predisposition Process Productivity Proteins Publishing Quality of life Regulation Retina Reverse Transcriptase Polymerase Chain Reaction Risk Seizures Slice Streptozocin Subgroup Synapses Testing Therapeutic Agents Type 2 diabetic United States Variant Viral Western Blotting cell type db/db mouse diabetic diabetic patient epileptiform extracellular hippocampal pyramidal neuron improved insight inward rectifier potassium channel mRNA Expression male mortality mouse model nervous system disorder neuronal circuitry neuronal excitability non-diabetic novel therapeutics patch clamp patient subsets protein expression response sex stem uptake

项目摘要

Epilepsy is one of the most common neurological disorders in the US. Diabetics are a subgroup of patients that are at increased risk of suffering from this condition, increasing their morbidity and mortality. Whereas, 9.3% of the United States population has diabetes. It has been shown that uncontrolled hyperglycemia (diabetes) increases the susceptibility to epileptiform-like activity in the brain but the mechanism is still unknown. There is a critical need in the identification a potential mechanism that may help link diabetes and seizures. Epilepsy is caused by a disruption of neuronal communication. One of the factors that may contribute to epileptiform activity is the accumulation of extracellular potassium [K+]o in active synaptic areas. Astrocytes provide support, deliver nutrients to neuronal circuits and maintain extracellular ion balance. Furthermore, they are one of the most abundant cell types in the brain and they have been highlighted in epilepsy mostly due to decreased capabilities in potassium uptake. One important well-characterized process that relates to epilepsy is the regulation of [K+]o. The Kir4.1 inwardly rectifying potassium channel (Kir4.1) located in astrocytes surrounding synapses largely carries out the process of potassium uptake. The rationale for the proposed study is based on our published data which shows that astrocytes from hippocampal brain slice from diabetic male mice display Kir4.1 channel protein downregulation and significant decrease in potassium uptake capability. The objective of this project is to find a relationship between Kir4.1 downregulation and seizure-like events in the brain of diabetic male and female mice considering sex as a biological variable. Therefore, our Central Hypothesis is that one of the major causes of the epileptic phenotype in diabetic patients is the inability to buffer excess [K+]o by astrocytes due to downregulation of the Kir4.1 channel protein. We will address this by measure astrocytic Kir4.1 channel mRNA and protein levels, test Kir4.1 channel activity in hippocampal astrocytes and assess the epileptiform activity in hippocampal pyramidal neurons in response to 4-aminopyridine application using electrophysiology in female mice. Finally, we will characterize and determine if reinstatement of Kir4.1 channels protein in hippocampal astrocytes via viral delivery will restore astrocytic Kir channel expression, membrane potential, barium sensitive currents and K+ and further correlate this with neuronal epileptiform-like activity in diabetic mice. These results will contribute to new information specifically to the knowledge of diabetes (high glucose) in the brain which may negatively contribute to neurological problems such as the neuronal hyperexcitability seen in epilepsy. Our main goal is to understand how hyperglycemia affects astrocytic homeostatic functions leading to neuronal hyperexcitability.

癫痫是美国最常见的神经系统疾病之一。糖尿病患者是一类