Ectopic Granule Cells in the Dentate Gyrus

描述（由申请人提供）：已经表明成年齿状回中颗粒细胞（GC）的出生后神经发生具有与认知和情绪调节相关的重要功能，并且出生后神经发生的损伤可能发生在许多疾病中。与大多数关于成人神经发生的研究相反，这些研究集中在GC所在的正常区域，颗粒细胞层，在这个提议中，我们建议一个不同的区域是重要的，相邻的门。我们认为，在各种病理条件下，成人出生的GC误迁移到门，这些异位GC（EGCs）引起功能障碍。 这一假说是基于对癫痫动物模型中EGCs的研究，其中发现门EGCs发育，并显示异常的兴奋性和回路。令人惊讶的是，我们现在已经在精神疾病，如阿尔茨海默病（AD）的动物模型中发现了门EGCs的证据。与此同时，其他实验室也报告称，精神分裂症和酗酒患者会出现成人出生GC的误迁移。在我们模拟AD的转基因小鼠的初步研究中，EGCs似乎出现异常的兴奋性和电路，因此我们假设它们会像癫痫动物模型一样破坏电路功能。我们也有初步的数据表明，EGCs存在于精神病患者的尸检标本。因此，在这个建议中，我们将试图表明，肺门EGCs不仅与癫痫有关，但精神疾病。我们假设EGCs在精神疾病中发展，因为负责这些条件的分子机制也破坏了控制GC迁移的正常线索。拟进行的实验将采用1）解剖学方法证明EGCs在精神疾病动物模型中的存在，2）切片电生理学方法证明EGCs在这些动物模型中具有异常的兴奋性和回路，3）行为学实验证明EGCs在体内伴随功能障碍，以及4）计算建模以显示EGC将在正常齿状回网络的计算模型中破坏齿状回的特定功能。 这些结果将是重要的，因为它们将为许多影响认知和行为的疾病的共同病理提供证据：齿状回门中的EGCs。这一见解可能导致新疗法的发展，以靶向迁移的分子机制。EGCs成像可能成为一种新的诊断策略。改进的治疗和诊断都很重要，因为许多精神疾病是复杂的，在诊断和治疗方面都存在困难。 公共卫生相关性：通常认为，出生后齿状回的神经发生可以改善认知功能和情绪，因此增加神经发生的速度是有益的。然而，我们认为，这种积极的影响可能不会发生在病理条件下存在，因为这些条件破坏了控制正常迁移的线索。因此，异位神经元可以发育并破坏功能，支持正常迁移的治疗策略将防止功能障碍。

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.