Faculty, Staff and Student Publications
Publication Date
6-1-2024
Journal
Progress in Neurobiology
Abstract
Recurrent seizures lead to accumulation of the activity-dependent transcription factor ∆FosB in hippocampal dentate granule cells in both mouse models of epilepsy and mouse models of Alzheimer's disease (AD), which is also associated with increased incidence of seizures. In patients with AD and related mouse models, the degree of ∆FosB accumulation corresponds with increasing severity of cognitive deficits. We previously found that ∆FosB impairs spatial memory in mice by epigenetically regulating expression of target genes such as calbindin that are involved in synaptic plasticity. However, the suppression of calbindin in conditions of neuronal hyperexcitability has been demonstrated to provide neuroprotection to dentate granule cells, indicating that ∆FosB may act over long timescales to coordinate neuroprotective pathways. To test this hypothesis, we used viral-mediated expression of ∆JunD to interfere with ∆FosB signaling over the course of several months in transgenic mice expressing mutant human amyloid precursor protein (APP), which exhibit spontaneous seizures and develop AD-related neuropathology and cognitive deficits. Our results demonstrate that persistent ∆FosB activity acts through discrete modes of hippocampal target gene regulation to modulate neuronal excitability, limit recurrent seizure activity, and provide neuroprotection to hippocampal dentate granule cells in APP mice.
Keywords
Animals, Humans, Male, Mice, Alzheimer Disease, Amyloid beta-Protein Precursor, Dentate Gyrus, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Neuroprotection, Proto-Oncogene Proteins c-fos, Seizures, Alzheimer’s disease, epilepsy, neuroprotection, hippocampus, ΔFosB, epigenetic
DOI
10.1016/j.pneurobio.2024.102612
PMID
38642602
PMCID
PMC11406539
PubMedCentral® Posted Date
6-1-2025
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes