Cognitive impairment is a devastating co-morbidity of epilepsy. However, the molecular mechanisms by which recurrent seizures induce cognitive impairments that persist even in seizure-free periods are not well understood. This gap in knowledge hampers the development of therapeutic interventions to reduce cognitive deficits associated with epilepsy. Our preliminary studies demonstrate that seizure-induced increase in hippocampal expression of the transcription factor ?FosB triggers a chain of events leading to epigenetic repression of a number of genes in the hippocampus, some of which are known to be critical for the induction of synaptic plasticity. Increasing seizure severity led to increasing expression of ?FosB that exerted long lasting epigenetic repression of gene expression, with detrimental consequences for hippocampal-dependent spatial memory. Such increases in ?FosB expression, epigenetic alterations, and associated spatial memory deficits were observed in a pharmacological kainate model of epilepsy as well as a transgenic mouse model of Alzheimer's disease (AD), both of which exhibit recurrent seizures. The goals of this proposal are to determine the precise mechanisms by which ?FosB induces epigenetic repression of key genes required for synaptic plasticity, and whether normalizing gene expression restores cognitive function in kainate and AD models with recurrent seizures. To achieve these goals, in Aim 1 we will characterize the dynamics of ?FosB expression, downstream gene repression, and cognitive deficits in kainate and AD mice.
In Aim 2, we will determine the mechanisms by which ?FosB induces chromatin modifications that regulate gene expression in kainate and AD mice.
In Aim 3, we will determine whether viral expression of a dominant negative antagonist of ?FosB blocks ?FosB's effects on gene expression in the hippocampus, and restores cognitive function in kainate and AD mice. Results from these studies will forge a new avenue of understanding how recurrent seizures impair cognitive function, and highlight a novel pathway for therapeutic targeting. In addition, they will provide novel insights into common mechanisms of cognitive impairment in any condition associated with recurrent seizures, such as AD. Given that epilepsy is a co-morbidity of a number of neurological conditions/diseases the results from our studies will have broad impact.
Recurrent seizures that occur in epilepsy and other neurological conditions such as Alzheimer's disease lead to memory loss and cognitive impairments that persist even in seizure-free periods. However, little is known about why this is the case, making it difficult to develop therapeutic strategies to improve cognitive function in conditions with recurrent seizures. Our goal is to determine how seizures produce long-lasting changes in gene expression in the hippocampus, a part of the brain that is critical for memory and cognition. Findings from these studies will provide critical information for designing therapies to prevent the pathological effects of recurrent seizures.
|You, Jason C; Stephens, Gabriel S; Fu, Chia-Hsuan et al. (2018) Genome-wide profiling reveals functional diversification of ?FosB gene targets in the hippocampus of an Alzheimer's disease mouse model. PLoS One 13:e0192508|
|Corbett, Brian F; You, Jason C; Zhang, Xiaohong et al. (2017) ?FosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer's Disease. Cell Rep 20:344-355|
|You, Jason C; Muralidharan, Kavitha; Park, Jin W et al. (2017) Epigenetic suppression of hippocampal calbindin-D28k by ?FosB drives seizure-related cognitive deficits. Nat Med 23:1377-1383|