Uncovering the role of SAP97 in synaptic function and schizophrenia.

揭示 SAP97 在突触功能和精神分裂症中的作用。

• 批准号: 10736790
• 负责人: Bruce Herring
• 金额: $ 45.13万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736790
• 关键词: 3q29; AMPA Receptors; Affect; Alternative Splicing; Alzheimer' s Disease; Animal Behavior; Animals; Antibodies; Behavior; Behavioral; Binding; Biological; Brain; Brain Diseases; Brain region; Clinical Data; Complex; Cytoplasmic Granules; DLG1 gene; Data; Dendrites; Development; Disease; Distal; Electrophysiology (science); Endoscopy; Episodic memory; Etiology; Exhibits; Functional disorder; Gene Expression; Genes; Genetic; Glutamates; Goals; Hippocampus; Human; Human Genetics; Imaging Device; Individual; Knowledge; Label; Laboratories; Lateral; Lead; Link; Medial; Memory; Mental disorders; Methods; Missense Mutation; Mission; Molecular; National Institute of Neurological Disorders and Stroke; Neurons; Pathologic; Pathology; Pathway interactions; Perforant Pathway; Play; Property; Protein Isoforms; Public Health; Reagent; Regulation; Research; Rodent; Rodent Model; Role; Schizophrenia; Severities; Specificity; Symptoms; Synapses; Techniques; Testing; Time; Variant; Work; autism spectrum disorder; dentate gyrus; genetic regulatory protein; high risk; hippocampal pyramidal neuron; imaging approach; immunoreactivity; in vivo; in vivo imaging; information processing; innovation; microdeletion; neurotransmission; novel therapeutic intervention; pre-clinical; response; schizophrenia risk; synaptic function; tool; trafficking; transmission process

PROJECT SUMMARY Preclinical and clinical data show elevated glutamatergic transmission and neuronal activity within the hippocampus during the early stages of schizophrenia development, and it is proposed that such elevations drive the progression of the disorder. However, the molecular and cellular mechanisms that give rise to schizophrenia- related elevations in hippocampal glutamatergic transmission are unknown. Recent human genetic data supports a connection between reduced DLG1 gene expression/function and schizophrenia. The DLG1 gene encodes the putative synaptic regulatory protein SAP97. However, a clear synaptic regulatory role for SAP97 has remained elusive. We have now, for the first time, identified a native synapse in the brain where SAP97 plays a critical and direct role in synaptic regulation. The long-term goal of our research is to understand how glutamatergic synapse dysfunction contributes to the development of psychiatric disorders. Our central hypothesis is that disruption of SAP97 function in dentate granule neurons (DG neurons) of the hippocampus produces pathological synaptic strengthening that contributes to schizophrenia etiology. Guided by strong preliminary data, we will pursue this hypothesis in three specific aims. In Aim 1, we will combine electrophysiological methods with brand new imaging tools to characterize pathway-specific roles of SAP97 in regulating glutamatergic neurotransmission and plasticity. In Aim 2, we will use a combination of newly generated antibodies, molecular biological and electrophysiological/imaging approaches to identify the roles of SAP97 subregions in governing SAP97’s subcellular localization and influence over glutamatergic synapse function in DG neurons. In Aim 3, we will deploy cutting-edge in vivo imaging tools in freely behaving animals in order to understand how hippocampal neuron activity is altered in rodents with compromised SAP97 function. The present proposal is innovative because it deploys new and powerful genetic, in vivo imaging, and behavioral analysis tools that will allow a precise characterization of a newly discovered role for SAP97 in regulating the function of native glutamatergic synapses in the hippocampus. The proposal is significant because it stands to identify synaptic pathology in a specific brain region that represents a common component in schizophrenia development. This proposal squarely meets the mission objectives of the NINDS given its focus on understanding glutamatergic synapse regulation and memory formation which are found to be disrupted in complex brain disorders.

项目摘要 临床前和临床数据表明，谷氨酸能传播和神经元活动升高 在精神分裂症发展的早期阶段，海马，并提议这种海拔驱动 该疾病的进展。然而，产生精神分裂症的分子和细胞机制 海马谷氨酸能传播的相关升高尚不清楚。最近的人类遗传数据支持 DLG1基因表达/功能和精神分裂症的降低之间的联系。 DLG1基因编码 推定的突触调节蛋白SAP97。但是，SAP97具有明确的突触调节作用 仍然难以捉摸。现在，我们第一次确定了SAP97扮演A的大脑中的本地突触 在突触调节中的关键和直接作用。我们研究的长期目标是了解如何 谷氨酸能突触功能障碍有助于精神疾病的发展。我们的中心 假设是海马的齿状颗粒神经元（DG神经元）中SAP97功能的破坏 产生病理性的突触增强，这有助于精神分裂症病因。在强者的指导下 初步数据，我们将以三个特定目标提出这一假设。在AIM 1中，我们将结合 具有全新成像工具的电生理方法，以表征SAP97的途径特定角色 调节谷氨酸能神经传递和可塑性。在AIM 2中，我们将使用新生成的组合 抗体，分子生物学和电生理/成像方法鉴定SAP97的作用 管理SAP97亚细胞定位的子区域，并影响谷氨酸能突触功能 DG神经元。在AIM 3中，我们将在自由行为动物中部署尖端的体内成像工具 了解SAP97功能受损的啮齿动物中海马神经元活性如何改变。这 目前的建议具有创新性，因为它部署了新的有力的遗传，体内成像和行为 分析工具将允许精确表征SAP97新发现的角色 海马中天然谷氨酸能突触的功能。该提议很重要，因为它代表 在特定的大脑区域中识别突触病理，代表精神分裂症中常见成分 发展。该提议正符合Ninds的任务目标，鉴于其关注 了解谷氨酸能突触调节和记忆形成，被发现被破坏 复杂的脑部疾病。