Early Seizure Activity Accelerates Depletion of Hippocampal Neural Stem Cells and Impairs Spatial Discrimination in an Alzheimer’s Disease Model

Abstract

Summary: Adult hippocampal neurogenesis has been reported to be decreased, increased, or not changed in Alzheimer’s disease (AD) patients and related transgenic mouse models. These disparate findings may relate to differences in disease stage, or the presence of seizures, which are associated with AD and can stimulate neurogenesis. In this study, we investigate a transgenic mouse model of AD that exhibits seizures similarly to AD patients and find that neurogenesis is increased in early stages of disease, as spontaneous seizures became evident, but is decreased below control levels as seizures recur. Treatment with the antiseizure drug levetiracetam restores neurogenesis and improves performance in a neurogenesis-associated spatial discrimination task. Our results suggest that seizures stimulate, and later accelerate the depletion of, the hippocampal neural stem cell pool. These results have implications for AD as well as any disorder accompanied by recurrent seizures, such as epilepsy. : The mechanisms that alter hippocampal neurogenesis in AD patients and mice are unclear. Fu et al. show that in a transgenic mouse model, spontaneous seizures stimulate neural stem cell (NSC) proliferation and accelerate depletion of a finite NSC pool. This process leads to neurogenesis that is increased early but decreased later in disease, coinciding with spatial discrimination deficits. Keywords: neurogenesis, Alzheimer, seizure, epilepsy, hippocampus, dentate gyrus, neural stem cell pool, cognition, memory, mouse model