Alzheimer?s disease (AD) is marked by progressive neurodegeneration and profound cognitive decline. How cognitive decline develops is not well-understood, especially regarding cognitive deficits that occur early in disease before robust neuropathology and neuron loss. Recent findings indicate that seizures contribute to hippocampal deficits and hasten cognitive decline, even at the earliest stages of AD. The incidence of seizures is 5-10x higher in AD patients than reference populations, and one study demonstrated subclinical epileptiform activity in over 42% of AD patients examined, which correlated well with the rate and severity of cognitive decline. Subclinical epileptiform activity and seizures have been observed also in transgenic mice that overexpress mutant human amyloid precursor protein (APP) and produce high levels of A?, well-characterized models used to study AD. Antiepileptic treatment ameliorates memory deficits in both AD patients and mouse models, indicating that seizures contribute to these deficits. Our lab recently reported that one mechanism by which seizures, even when infrequent, cause persistent memory deficits is via activity-dependent expression of the transcription factor ?FosB in the dentate gyrus (DG). We found that ?FosB, which has an unusually long half-life (>8 days), epigenetically regulates expression of genes that are necessary for plasticity and memory. Our recent ChIP-sequencing analyses demonstrated that in addition to suppressing memory-related genes, ?FosB also represses genes that enhance neuronal excitability, and thereby can limit DG excitability. Together, these results indicate that seizure-induced ?FosB expression caps DG excitability but at the cost of plasticity and cognitive function. We identified a novel target of ?FosB in the hippocampus to be the Ca2+ activated Cl- channel Ano2. We found strong ?FosB binding to the Ano2 gene, along with histone deacetylation, and reduced Ano2 mRNA and protein levels in DG of APP mice. My preliminary data indicate that AAV-mediated restoration of Ano2 expression in DG of APP mice may worsen seizure activity and disrupt hippocampal function, consistent with the hypothesis that epigenetic suppression of Ano2 expression may be an endogenous pathway by which ?FosB can limit neuronal excitability and possibly seizure activity. The goals of this proposal are to determine if ?FosB-mediated alterations in DG excitability affect seizures in APP mice, and if they do so by regulating levels of Ano2. To this end, I will 1) determine if blocking ?FosB signaling in the DG alters seizure activity in APP mice, 2) characterize alterations in Ano2 expression in APP mice and test the role of ?FosB, and 3) test if restoring Ano2 in the DG of APP mice alters seizures and/or hippocampal function. If the excitability-related pathways regulated by ?FosB can be identified and isolated from ?FosB target pathways that impair cognition, we may be able to develop novel therapeutic strategies that both stabilize excitability and improve cognition in disorders accompanied by recurrent seizures, such as AD and epilepsy.
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 how this process occurs, making it difficult to develop targeted therapies that improve cognition in conditions with recurrent seizures. My goal is to determine how seizures produce long-lasting changes in gene expression and function in the hippocampus, a brain region that is critical for memory and cognition, so that we can design therapies to prevent the pathological effects of recurrent seizures in Alzheimer?s disease and in epilepsy.
