Accelerated depletion of hippocampal neural stem cells in neurological disease

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DESCRIPTION (provided by applicant): Adult-born neurons in the dentate gyrus (DG) play critical roles in learning, memory, depression, and anxiety. Both Alzheimer's disease (AD) and epilepsy are associated with marked alterations in neurogenesis, which may contribute to cognitive and psychiatric symptoms that are key features of both diseases. Recurrent seizures, which are characteristic of both AD and epilepsy, may critical in the (dys)-regulation of neurogenesis and downstream cognitive impairments. Acute seizure activity stimulates neurogenesis in rodents and humans, but chronic epilepsy is associated with decreased neurogenesis. Why acute and chronic seizures are associated with opposing effects on neurogenesis, and how this affects cognition, is unknown. Recent findings that neural stem cells in the mouse DG are "disposable" rather than self-renewing may provide an explanation. Upon exiting the quiescent state, these adult DG neural stem cells undergo a series of asymmetric divisions to produce dividing progeny destined to become neurons, and then terminally differentiate into astrocytes. This "disposable stem cell" model accounts for the age-related disappearance of DG neural stem cells, appearance of new astrocytes, and age-related decline in neurogenesis. Such a model would predict that the robust increases in neurogenesis triggered by acute seizures accelerate division-coupled depletion of the neural stem cell pool, leading to reduced neurogenic potential in conditions with recurrent seizures such as AD and epilepsy. Our preliminary data support the hypothesis that loss of DG neural stem cells is accelerated in transgenic mice expressing human amyloid precursor protein (APP), a well-characterized model of AD with spontaneous seizures, and that accelerated loss affects specific cognitive functions that are regulated by adult- born DG neurons. We found similar results in the kainate model of epilepsy; moreover, treatment of APP mice with an anti-epileptic drug appeared to delay the rate of loss, supporting a role for seizures. Building on these preliminary studies, in Aim 1, we will establish that the DG neural stem cell pool undergoes accelerated division-coupled depletion that is commensurate with seizure activity and cognitive deficits in APP mice; in Aim 2 we will determine whether treatment with an anti-epileptic drug prevents depletion of the DG neural stem cell pool and ameliorates performance on a DG-dependent behavioral task; in Aim 3 we will assess whether pharmacologically-induced seizures in wild-type mice also induce division-coupled depletion of the DG neural stem cell pool and deficits in DG function. Determining if seizures accelerate division-coupled depletion of the DG neural stem cell pool will shed new light on understanding the processes that drive both normal use, and pathological depletion, of neural stem cells. The answer will have a major impact on determining the stages of neurogenesis that are most advantageous to focus on for therapeutic strategies. This is an essential step in achieving two major long-term goals: 1) prevent pathological effects of conditions that impact neurogenesis, 2) harness the power of neurogenesis as a treatment for devastating conditions like AD and epilepsy.