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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

基本信息

批准号：
10057937
负责人：
ROBERT BRENNER
金额：
$ 15.44万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
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/10057937
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

项目摘要

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.

项目概要尽管癫痫被诊断为无端癫痫发作，但人们普遍认为癫痫发作可以诱发在癫痫个体中，内源性和外源性兴奋剂。压力和焦虑是其中最严重的经常报道的癫痫患者癫痫发作的诱因。了解病理生理学焦虑引起的癫痫发作可以极大地有益于癫痫患者的治疗。在这里，我们介绍焦虑诱发癫痫发作的新型小鼠模型的初步数据。该模型受 cre 诱导调节含有癫痫突变的人 BK 型钾通道基因（D369G 转基因）的表达。初步研究表明，D369G 小鼠的焦虑程度有所增加，并且处理引起的癫痫发作也有所增加。我们的首要假设是，这些转基因小鼠将作为焦虑诱发癫痫发作的模型癫痫。作为了解焦虑引起的癫痫发作的第一步，我们提出了一项 R03 试点研究来确定 D369G 表达引起癫痫发作的大脑区域。我们提出两个目标。对于目标 1，我们将更彻底地表征小鼠表型并筛选剩余的创始人系以进行处理- 诱发癫痫发作。通过将 D369G 系与 BK 通道敲除小鼠杂交，我们将消除内源性表达并确定 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性的 cre 驱动线来确定大脑区域负责 D369G 表型。我们假设操作引起的癫痫发作是由 D369G 介导的 BK 通道在海马兴奋性细胞中发育后表达。使用颞和组织- 我们将检查特定的 cre 驱动系 1) 该表型是否需要产前或产后表达，2) 是否兴奋性或抑制性神经元赋予表型，或 3) 如果海马或杏仁核中的表达赋予表型增加焦虑和处理诱发的癫痫发作。该提案的成功将为未来的发展奠定基础关于所识别的大脑区域的活动如何与焦虑相交叉的深度电生理学研究促进癫痫发作，并可能提供药物靶点来预防或限制应激诱发的癫痫发作。