Abstracts

Rationale: Recurrent seizure activity is associated with cognitive deficits in many neurological disorders, including epilepsy and Alzheimer’s disease (AD). We reported that seizures induce expression of ∆FosB, a transcription factor with an unusually long half-life that epigenetically alters gene expression and persistently impairs cognition in patients with epilepsy or AD (and respective mouse models). Yet, whether ∆FosB binds to the same target genes and regulates similar functions across different neurological disorders with recurrent seizures is unclear. Determining which ∆FosB target genes are shared, and which are unique, in specific disease contexts may reveal novel pathways regulated by seizures that could be targeted to treat multiple (or specific) conditions with recurrent seizures. Methods: To examine recurrent seizure activity in different disease contexts, we used either wild-type mice injected with pilocarpine (Pilo mice) or a transgenic mouse model of Alzheimer’s disease that exhibits spontaneous recurrent seizures (human amyloid precursor protein mice, referred to as APP mice). We performed hippocampal ChIP-sequencing to identify and compare ∆FosB target genes in Pilo mice and APP mice. Using network profiling and gene clustering methods, we examined the functional landscapes of ∆FosB target genes in Pilo mice, saline control mice, APP mice, and nontransgenic control mice, respectively. Results: Clusters of genes related to neuronal development and neurogenesis were consistently represented in ∆FosB target gene networks in all groups of mice (Pilo mice and saline controls, APP mice and nontransgenic controls). However, Pilo mice and APP mice shared ∆FosB target genes that regulate neuronal excitability, plasticity, and glutamatergic signaling; these targets were not bound by ∆FosB in respective control mice. We also found that some ∆FosB target genes were represented only in either Pilo or APP mice, suggesting the existence of disease context-specific ∆FosB target genes that can regulate unique functional domains. Conclusions: Our results demonstrate that seizure-induced ∆FosB can bind similar target genes in different disease contexts, but can also target other genes selectively which may drive functional alterations in specific disease contexts. Determining the mechanisms that give rise to both the similarities and differences, such as alterations in chromatin accessibility or transcriptional binding partners, may reveal novel insights into the control of gene regulation and neuronal function in diverse neurological disorders with recurrent seizure activity. Funding: This work was supported by NIH NS085171 (JC).