Neuronal Hyperactivity Accelerates Depletion of Neural Stem Cells and Impairs Hippocampal Neurogenesis

•Kainic acid injections into hippocampus model neuronal hyperactivity in mice•At low doses, without seizure activity, rNSCs divide asymmetrically•At high doses, with seizures, rNSCs divide symmetrically into reactive astrocytes•Both models deplete rNSCs and impair hippocampal neurogenesis

SummaryAdult hippocampal neurogenesis is believed to maintain a range of cognitive functions, many of which decline with age. We recently reported that radial neural stem cells (rNSCs) in the hippocampus undergo activation-dependent conversion into astrocytes, a mechanism that over time contributes to a reduction in the rNSC population. Here, we injected low and high levels of kainic acid (KA) in the dentate gyrus to assess whether neuronal hyperexcitation, a hallmark of epileptic disorders, could accelerate this conversion. At low levels of KA, generating epileptiform activity without seizures, we indeed found increased rNSC activation and conversion into astrocytes. At high levels, generating sustained epileptic seizures, however, we find that rNSCs divide symmetrically and that both mother and daughter cells convert into reactive astrocytes. Our results demonstrate that a threshold response for neuronal hyperexcitation provokes a dramatic shift in rNSC function, which impairs adult hippocampal neurogenesis in the long term.

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