Genes Bound by ΔFosB in Different Conditions With Recurrent Seizures Regulate Similar Neuronal Functions

Abstract

Seizure incidence is increased in Alzheimer's disease (AD) patients and mouse models, and treatment with the antiseizure drug levetiracetam improves cognition. We reported that one mechanism by which seizures can exert persistent effects on cognition is through accumulation of FosB, a transcription factor with a long half-life. Even the infrequent seizures that spontaneously occur in transgenic mice expressing human amyloid precursor protein (APP) lead to persistent increases in FosB in the hippocampus, similar to what we observed in patients with AD or temporal lobe epilepsy. FosB epigenetically regulates expression of target genes, however, whether FosB targets the same genes when induced by seizures in different neurological conditions is not clear. We performed ChIP-sequencing to assess the repertoire of FosB target genes in APP mice and in pilocarpine-treated wildtype mice (Pilo mice), a pharmacological model of epilepsy. These mouse models allowed us to compare AD, in which seizures occur in the context of high levels of amyloid beta, and epilepsy, in which recurrent seizures occur without AD-specific pathophysiology. Network profiling of genes bound by FosB in APP mice, Pilo mice, and respective control mice revealed that functional domains modulated by FosB in the hippocampus are expanded and diversified in APP and Pilo mice (vs. respective controls). Domains of interest in both disease contexts involved neuronal excitability and neurotransmission, neurogenesis, chromatin remodeling, and cellular stress and neuroinflammation. To assess the gene targets bound by FosB regardless of seizure etiology, we focused on 442 genes with significant FosB binding in both APP and Pilo mice (vs. respective controls). Functional analyses identified pathways that regulate membrane potential, glutamatergic signaling, calcium homeostasis, complement activation, neuron-glia population maintenance, and chromatin dynamics. RNA-sequencing and qPCR measurements in independent mice detected altered expression of several FosB targets shared in APP and Pilo mice. Our findings indicate that seizure-induced FosB can bind genes in patterns that depend on seizure etiology, but can bind other genes regardless of seizure etiology. Understanding

Altered Hippocampal Activation in Seizure-ProneCACNA2D2Knock-out Mice

“…Another member of the Fos family of immediate early genes, FosB, is similarly expressed in an activity-dependent manner, and in particular, a splice variant of the FosB gene (ΔFosB) is commonly used as a marker of chronically elevated neuronal activity due to its significantly extended protein half-life ( Stephens et al, 2020 ). We stained sections from the WT and CACNA2D2 KO mice above for ΔFosB to evaluate whether KO mice have more chronically elevated levels of activity.…”

Dentate Gyrus Granule Cells Show Stability of BDNF Protein Expression in Mossy Fiber Axons with Age, and Resistance to Alzheimer’s Disease Neuropathology in a Mouse Model

“…In AD mouse models, there is increased excitability of GCs ( Nenov et al, 2015 ; Kim et al, 2021 ; Smith et al, 2022 ) and GCs specifically ( Minkeviciene et al, 2009 ; Alcantara-Gonzalez et al, 2021 ). When excitability is sufficiently elevated, seizures occur and the seizures increase GC ΔFosB ( You et al, 2017 ; Fu et al, 2019 ; Stephens et al, 2020 ). Consistent with these studies, we found that Tg2576 GCs had elevated ΔFosB.…”

Elementary Pathophysiology, Treatment, Risk Factor of Alzheimer’s Disease

“…In AD patients with a presenilin mutation, defects in the lysosomal proteolysis machinery were found [133]. Downregulation of Beclin-1, an important regulator of autophagy start, resulted in the build-up of both intraneuronal and extracellular A deposits in an APP-overexpressing mouse model, followed by significant neurodegeneration [134][135].…”