A novel mouse model for anxiety-induced seizures

一种用于焦虑诱发癫痫发作的新型小鼠模型

• 批准号: 10244725
• 负责人: ROBERT BRENNER
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244725
• 关键词: Ablation; Affect; Amygdaloid structure; Anxiety; Bacterial Artificial Chromosomes; Behavior; Brain region; Cells; Cre driver; Cytoplasmic Granules; Data; Development; Diagnosis; Disease; Drug Targeting; Electroencephalography; Electrophysiology (science); Enterobacteria phage P1 Cre recombinase; Epilepsy; Functional disorder; Future; Gene Expression; Generalized Epilepsy; Genes; Genetic; Genetic Polymorphism; Goals; Hippocampus (Brain); Human; Individual; Intuition; Knockout Mice; Link; Mediating; Modeling; Mus; Mutation; Neocortex; Neurons; Patients; Pattern; Pentylenetetrazole; Phenotype; Picrotoxin; Pilot Projects; Population; Potassium Channel; Principal Investigator; Pyramidal Cells; Reflex action; Regulation; Reporting; Research; Seizures; Severities; Stress; Tamoxifen; Temporal Lobe; Tissues; Tonic - clonic seizures; Transcriptional Regulation; Transgenes; Transgenic Mice; Transgenic Organisms; behavior test; cell type; channel blockers; dentate gyrus; excitatory neuron; experimental study; fear memory; field study; gain of function; genomic locus; inhibitory neuron; large-conductance calcium-activated potassium channels; mouse model; nervous system disorder; neuronal circuitry; neuronal excitability; novel; paxilline; postnatal; prenatal; prevent; promoter; success; transgene expression

Project Summary Although epilepsy is diagnosed as unprovoked seizures, it is generally accepted that seizures can be precipitated in epileptic individuals by endogenous and exogenous stimulants. Stress and anxiety are among the most frequently reported precipitants for seizures in epileptic individuals. Understanding the pathophysiology of anxiety-induced seizures can dramatically benefit management of epileptic patients. Here, we present preliminary data for a novel mouse model for anxiety-induced seizures. The model is regulated by cre-induced expression of a human BK-type potassium channel gene containing an epilepsy mutation (D369G transgene). Preliminary studies indicate the D369G mice have increased anxiety, and handling-induced epileptic seizures. Our overarching hypothesis is that these transgenic mice will serve as a model for anxiety-induced seizures in epilepsy. As a first step to understanding anxiety-induced seizures, we propose an R03 pilot study to identify the regions of the brain where expression of the D369G causes seizures. We propose two aims. For aim 1, we will more thoroughly characterize the mouse phenotypes and screen the remaining founder lines for handling- induced seizures. By also crossing D369G lines to the BK channel knockout mice, we will eliminate endogenous expression and determine if D369G transgene expression reflects the normal BK channel expression pattern. For aim 2, we will use tissue and developmental-specific cre driver lines to determine the brain region/s responsible for the D369G phenotype. We hypothesize that handling-induced seizures are mediated by D369G BK channel post-development expression in excitatory cells of the hippocampus. Using temporal and tissue- specific cre driver lines we will examine 1) if prenatal or postnatal expression is required for the phenotype, 2) if excitatory or inhibitory neurons confer the phenotype, or 3) if expression in the hippocampus or amygdala confer increased anxiety and handling induced seizures. Success of this proposal will create a foothold for future in- depth electrophysiology studies regarding how activity in the identified brain region intersects with anxiety to precipitate seizures, and potentially provide drug targets to prevent or limit stress-induced seizure onset.

项目摘要 虽然癫痫被诊断为无缘无故的癫痫发作，但人们普遍认为癫痫发作是可以突然发生的。 在癫痫患者中由内源性和外源性兴奋剂引起。压力和焦虑是最重要的 经常报道的癫痫患者癫痫发作的沉淀剂。了解心绞痛的病理生理学 焦虑导致的癫痫发作对癫痫患者的治疗大有裨益。在这里，我们向大家介绍 一种新的焦虑诱发癫痫小鼠模型的初步数据。该模型是由cre诱导的。 含有癫痫突变的人BK型钾通道基因(D369G转基因)的表达 初步研究表明，D369G小鼠焦虑增加，处理导致癫痫发作。 我们的主要假设是，这些转基因小鼠将作为焦虑诱导癫痫发作的模型。 癫痫。作为理解焦虑诱发癫痫的第一步，我们建议进行一项R03试点研究，以确定 大脑中表达D369G导致癫痫发作的区域。我们提出了两个目标。对于目标1，我们将 更彻底地描述鼠标的表型，并筛选出剩余的方正线条以供处理- 诱发性癫痫发作。通过将D369G系与BK通道基因敲除小鼠杂交，我们将消除内源性 并确定D369G转基因表达是否反映正常的BK通道表达模式。 对于目标2，我们将使用组织和发育特异的cre驱动线来确定大脑区域/S 负责D369G的表型。我们假设D369G介导了处理诱发的癫痫发作 BK通道发育后在海马区兴奋性细胞中的表达利用时间和组织- 我们将检查特定的cre驱动系1)表型是否需要产前或出生后表达，2)是否 兴奋性或抑制性神经元提供表型，或3)如果在海马区或杏仁核中表达 增加焦虑和处理导致的癫痫发作。这项建议的成功将为未来在以下方面创造一个立足点- 关于确定的大脑区域的活动如何与焦虑相交的深入电生理学研究 促进癫痫发作，并有可能提供药物靶点，以防止或限制应激诱导的癫痫发作。