Reverse Translation of Psychosis - associated Hippocampal Hyperactivity in the mouse

摘要 海马体与许多与正常记忆相关的功能有关， 几种疾病。本实验室研究了海马与精神分裂症（SZ）病理生理学的关系 使用认知和行为结果（1-3）和大脑图像分析（4-6）。这些一致表明， 海马（Hipp）活性在精神分裂症性精神病（SZ）中升高，特别是在早期疾病中。测试 这种活动过度的分子基础，我们检查了人死后海马组织的亚区， 对照健康和精神分裂症病例，使用兴奋性和抑制性突触标记和高尔基体。我们 发现仅限于齿状回（DG）的GluN 1减少，CA 3中突触强度标记物增加 这些变化与Lee等人（7）在海马组织中报告的观察结果一致。 细胞培养物（见A.1）。Lee表明，CA 3锥体细胞敏感性是由 来自DG的传入输入，传入输入减少与锥体细胞活动增加相关。我们有 我能够使用DG选择性GluN 1敲除在小鼠中重现这种人类特异性SZ病理 （KO）（8）.这种反向翻译小鼠KO证明了Hipp的过度活跃和Hipp介导的细胞凋亡的改变。 行为（8）。我们正在DG中试验抑制性DREADD技术，以模拟DG选择性GluN 1 KO 小鼠和看到的证据，一个敏感的时期，在'中毒'，当减少DG活动可以刺激 CA 3/CA 1过度活跃。在KO动物中无法分辨该时间相，因此我们之前未发现 只能用DREADDs来研究这些实验的目的是因果定义的机制 作为使用DREADD构建体的小鼠中暂时DG功能减退的神经生物学结果的基础， 并显示全脑变化的程度、发展和脆弱性的关键时期。找到了 在KO小鼠中Hipp投射区域过度活跃的离散回路中，我们将测试人类SZ与HC组织， 这些地区的证据多动症和连贯性与Hipp。目标是建立一个模型， 海马过度活跃影响行为和大脑病理学，特别是这种组织病理学如何能够 支持异常记忆的精神病内容

ABSTRACT The hippocampus has been implicated in numerous functions related to normal memory and its dysfunction in several diseases. Our lab has investigated the hippocampus in relation to schizophrenia (SZ) pathophysiology using cognitive and behavioral outcomes(1-3) and brain image analyses(4-6). These consistently show that hippocampal (Hipp) activity is elevated in schizophrenic psychosis (SZ), especially in early illness. To test the molecular basis of this hyperactivity, we examined human postmortem hippocampal tissue by subfield, contrasting healthy and schizophrenia cases, using excitatory and inhibitory synaptic markers and Golgi. We found a reduction in GluN1 limited to dentate gyrus (DG) and an increase in markers of synaptic strength in CA3 in the SZ tissue; these changes are consistent with the observations that Lee et al(7) reported in hippocampal cell cultures (see A.1). Lee showed that CA3 pyramidal cell sensitivity is inversely and powerfully controlled by afferent input from DG, with decreased afferent input associated with increased pyramidal cell activity. We have been able to recapitulate this human-specific SZ pathology in a mouse using a DG-selective GluN1 knock out (KO)(8). This back-translation mouse KO demonstrated Hipp hyperactivity and alterations in Hipp-mediated behaviors (8). We are piloting an inhibitory DREADD technique in DG to mimic the DG-selective GluN1 KO mouse and saw evidence of a sensitive period during ‘adolescence’, when reduced DG activity could stimulate hyperactivity in CA3/CA1. This time phase cannot be resolved in the KO animal, so we had not seen it before and can only study it using DREADDs. The goal of these experiments are to causally define the mechanisms underlying the neurobiological outcomes of temporary DG hypofunction in mouse using DREADD constructs, and to show the extent, development, and critical periods of vulnerability of brain-wide changes. Having found a discrete circuit of Hipp projection regions hyperactive in the KO mouse, we will test human SZ vs HC tissue in these regions for evidence of hyperactivity and coherence with Hipp. The goal is to build a model of how hippocampal hyperactivity affects behavior and brain pathology, and specifically how this tissue pathology could support aberrant memories with psychotic content.