HB-EGF and zinc activate EGFR to induce reactive neural stem cells in the mouse hippocampus after seizures

Abstract

Hippocampal seizures mimicking mesial temporal lobe epilepsy (MTLE) cause a profound disruption of the adult neurogenic niche in mice. Seizures provoke neural stem cells to switch to a reactive phenotype (reactive-neural stem cells, React-NSCs)) characterized by multibranched hypertrophic morphology, massive activation to enter mitosis, symmetric division and final differentiation into reactive astrocytes. As a result, neurogenesis is chronically impaired. Here we, using a mouse model of MTLE, show that the epidermal growth factor receptor (EGFR) signalization pathway is key for the induction of React-NSCs and that its inhibition exerts a beneficial effect on the neurogenic niche. We show that during the initial days after the induction of seizures by a single intrahippocampal injection of kainic acid, a strong release of zinc and heparin-binding epidermal growth factor, both activators of the EGFR signalization pathway in neural stem cells, is produced. Administration of the EGFR inhibitor gefitinib, a chemotherapeutic in clinical phase IV, prevents the induction of React-NSCs and preserves neurogenesis. SignificanceIn mouse models of MTLE-HS, seizures cause a profound disruption of the hippocampal neurogenic niche and neurogenesis results chronically impaired, in agreement with what occurs in the human MTLE-HS hippocampus. Thus, the normal cognitive functions associated with neurogenesis are altered, but also the endogenous regenerative capacity that could compensate the high rate of neurons in the granule cell layer of the dentate gyrus. We provide here for the first time a molecular mechanism (the EGFR transduction pathway) regulating the induction of React-NSCs.