PROJECT SUMMARY/ABSTRACT
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 Aß, 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.