Role of deltaFosB in hippocampal gene expression and function in neurological disease

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Project Summary Cognitive impairment is a devastating co-morbidity of conditions with recurrent seizures, such as Alzheimer's disease and epilepsy, which persists even in seizure-free periods. We recently published that one critical reason for this is that seizures induce dentate gyrus (DG) expression of ∆FosB, a transcription factor that epigenetically suppresses key target genes that are crucial for plasticity and memory. ∆FosB expression is associated with cognitive deficits in patients and mouse models of epilepsy as well as Alzheimer's disease, demonstrating common mechanisms of cognitive dysfunction in conditions with seizures. Our new studies indicate ∆FosB acts on more than memory-related genes; it also represses genes that enhance intrinsic excitability, and thereby limits overall DG excitability. These findings indicate that seizure-induced ∆FosB expression is a “double-edged sword” that caps DG excitability, but at the cost of plasticity and cognitive function. Our goals are to build a comprehensive understanding of functional domains regulated by ∆FosB in the hippocampus, and identify novel strategies to improve cognition but maintain regulation of neuronal excitability in conditions with seizures, such as Alzheimer's disease and epilepsy. We previously used hypothesis-driven approaches to identify ∆FosB targets in hippocampus, but it was necessary to also obtain an unbiased, comprehensive view of ∆FosB in seizure-related conditions. To do so, we performed ChIP- sequencing to identify all genes bound by ∆FosB in the hippocampus of a well-characterized transgenic mouse model of Alzheimer's disease (AD mice) that exhibits recurrent seizures and high ∆FosB levels. In AD mice, ∆FosB bound to a novel network of genes involved in multiple aspects of neuronal excitability. Many of these genes were also bound by ∆FosB in hippocampus of wild-type mice treated with pilocarpine, a pharmacological model of epilepsy. In wild-type mice, AAV-mediated overexpression of ∆FosB decreased excitability whereas ∆JunD, a dominant negative antagonist of ∆FosB, increased excitability. Notably, long- term blockade of ∆FosB signaling in DG of AD mice changed the phenotype of their seizures from primarily nonconvulsive to primarily convulsive, supporting the theory that the typically low excitability and sparse activation of DG cells acts as a filter or gate that restricts epileptogenesis. Our work indicates ∆FosB plays critical roles in neuronal function in conditions with recurrent seizures. Understanding the mechanisms by which ∆FosB coordinately regulates expression of genes that control synaptic plasticity or neuronal excitability may reveal novel therapeutic strategies to reduce epileptogenesis while improving cognition. To this end, we will examine both Alzheimer's mice and pilocarpine mice to: 1) Investigate the role of ∆FosB in controlling intrinsic and network excitability of the DG, 2) identify and characterize the repertoire of hippocampal genes targeted by ∆FosB to control excitability, and 3) test whether specific ∆FosB target genes are key determinants of DG excitability and cognition.