A novel mouse model for anxiety-induced seizures

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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.