Ectopic Granule Cells in the Dentate Gyrus

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DESCRIPTION (provided by applicant): It has been suggested that postnatal neurogenesis of granule cells (GCs) in the adult dentate gyrus serves important functions related to cognition and mood regulation, and that impairments in postnatal neurogenesis may occur in many diseases. In contrast to most research about adult neurogenesis, which focuses on the normal area where GCs are located, the granule cell layer, in this proposal we suggest a different area is important, the adjacent hilus. We propose that, in a variety of pathological conditions, adult-born GCs mismigrate into the hilus, and these ectopic GCs (EGCs) cause dysfunction. This hypothesis is based on studies of EGCs in an animal model of epilepsy, where it was found that hilar EGCs develop, and display abnormal excitability and circuitry. Surprisingly, we have now found evidence for hilar EGCs in animal models of psychiatric illness, such as Alzheimer's disease (AD). In parallel, other laboratories have reported that mismigration of adult-born GCs occurs in schizophrenia and alcoholism. In our pilot studies from transgenic mice that simulate AD, EGCs appear to develop abnormal excitability and circuitry, so we hypothesize that they will disrupt circuit function like they do in animal models of epilepsy. We also have preliminary data suggesting that EGCs are present in postmortem specimens from patients with psychiatric illness. Therefore, in this proposal we will attempt to show that hilar EGCs are not only relevant to epilepsy, but psychiatric disease. We hypothesize that EGCs develop in psychiatric disorders because the molecular mechanisms that are responsible for these conditions also disrupt the normal cues that control migration of GCs. The experiments that are proposed will use 1) anatomical approaches to prove that EGCs exist in animal models of psychiatric diseases, 2) slice electrophysiology to prove the EGCs have abnormal excitability and circuitry in these animal models, 3) behavioral experiments to prove the EGCs are accompanied by dysfunction in vivo, and 4) computational modeling to show that EGCs will disrupt specific functions of the dentate gyrus in a computational model of the normal dentate gyrus network. The results would be significant because they would provide evidence for a common pathology across many diseases that affect cognition and behavior: EGCs in the hilus of the dentate gyrus. This insight could lead to the development of new therapeutics to target the molecular mechanisms of migration. Imaging EGCs could become a new diagnostic strategy. Improved therapeutics and diagnostics are both important because many psychiatric disorders are complex, presenting difficulties both in diagnosis as well as treatment. PUBLIC HEALTH RELEVANCE: It is often assumed that postnatal neurogenesis in the dentate gyrus improves cognitive function and mood, so increasing the rate of neurogenesis is beneficial. However, we suggest that this positive effect may not occur when pathological conditions exist, because these conditions disrupt the cues that control normal migration. Therefore, ectopic neurons can develop and disrupt function, and therapeutic strategies that support normal migration would prevent dysfunction.