Sp4 pathway in hippocampus modulates sensorimotor gating

海马 Sp4 通路调节感觉运动门控

• 批准号: 7163823
• 负责人: MARK A GEYER
• 金额: $ 22.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7163823
• 关键词: 7p15; A Mouse; Ablation; Adult; Affect; Animal Model; Animals; Attention deficit hyperactivity disorder; Autistic Disorder; Behavior; Behavioral; Bipolar Disorder; Brain; Brain Diseases; Breeding; Cells; Chromosomes; Clinical; Complex; Computer information processing; Cultured Cells; DRD1 gene; Deformity; Disease; Disruption; Dopamine; Dopamine Antagonists; Dopamine D1 Receptor; Down-Regulation; Drosophila genus; Environment; Family; Functional disorder; Future; G Protein-Coupled Receptor Signaling; G protein coupled receptor kinase; Gene Expression; Genes; Genetic; Glutamates; Hippocampus (Brain); Homologous Gene; Human; Internal Ribosome Entry Site; Knock-out; Knockout Mice; Maps; Measures; Mediating; Memory; Memory impairment; Mental disorders; Modeling; Molecular; Molecular Abnormality; Molecular Probes; Mus; Mutant Strains Mice; Neural Pathways; Neurotrophin 3; Numbers; Panic Disorder; Pathway interactions; Phenotype; Play; Predisposition; Rattus; Receptor Gene; Research Personnel; Rodent; Role; Schizophrenia; Sensory; Signal Pathway; Stimulus; System; Tamoxifen; Testing; Untranslated Regions; Virus; Work; base; dentate gyrus; desensitization; desmoplakin; endophenotype; genetic manipulation; granule cell; insight; mutant; neural circuit; neuropsychiatry; novel; prepulse inhibition; receptor; research study; response; restoration; transcription factor

DESCRIPTION (provided by applicant): Hippocampal abnormalities are important susceptibility factors for several human psychiatric disorders. Sensorimotor gating, assessed by prepulse inhibition of startle, is reduced in and provides a cross-species endophenotype for a group of psychiatric gating disorders, including schizophrenia, bipolar disorder, autism, and ADHD. In preliminary work, hypomorphic Sp4 mutant mice displayed vacuolization in the hippocampal dentate gyrus, reduced expression of the Grk4 gene in the hippocampus and cortex, robust deficits in sensorimotor gating and contextual memory, and decreased exploration of novel environments. The molecular, hippocampal, and behavioral abnormalities of the Sp4 mutant mice mimic several phenotypes for neuropsychiatric gating disorders. Specific Aim 1 will assess the cell autonomous roles of the Sp4 gene in the vacuolization of dentate gyrus, and the associated deficits in sensorimotor gating and contextual memory. A mouse line will be created with an inducible cre-ERT2 gene fused within the 3' UTR of the endogenous Desmoplakin (Dsp) gene by internal ribosome entry site without knocking-out Dsp expression. Tamoxifen will be used to activate the ere that in turn will reactivate or ablate the Sp4 expression in dentate granule cells. Hippocampal structural and functional abnormalities will be assessed in these rescue or conditional knockout mice. Specific Aim 2 will identify Sp4-mediated genetic pathways in the hippocampus that subserve novel object exploration. Studies will (a) further analyze the defective novelty exploration of the hypomorphic Sp4 mice in established paradigms; (b) examine whether the restoration or ablation of Sp4 expression in the dentate granule cells (Aim 1) can rescue or cause the defective novelty response. Specific Aim 3 will examine the role of the Grk4-mediated signaling pathway in the modulation of sensorimotor gating in Sp4 hypomorphic mice, using both pharmacological and genetic approaches. Cell culture experiments will examine Grk4-mediated desensitization of both dopamine D1 and mGluRI receptors in the Sp4 mutant hippocampal cells. Antagonists of dopamine D1 and mGluRI receptors will be administered to the hypomorphic Sp4 mutant mice to test for reversal of the prepulse inhibition deficit. To evaluate the disruption of Grk4-mediated GPCR signaling pathway in the modulation of sensorimotor gating and hippocampal vacuolization, double knockout mice combining the Sp4 deletion with either dopamine D1 or mGluRI receptor genes will be generated. These experiments will yield novel insights into genetic pathways within the hippocampus that underlie behavioral abnormalities relevant to several psychiatric disorders.

描述（由申请人提供）：海马异常是多种人类精神疾病的重要易感因素。通过惊吓的前脉冲抑制来评估感觉运动门控，它在一组精神门控疾病中减少并提供跨物种内表型，包括精神分裂症、双相情感障碍、自闭症和多动症。在初步研究中，低等位Sp4突变小鼠的海马齿状回出现空泡化，海马和皮质中Grk4基因的表达减少，感觉运动门控和情境记忆的严重缺陷，以及对新环境的探索减少。 Sp4突变小鼠的分子、海马和行为异常模仿了神经精神门控障碍的几种表型。具体目标 1 将评估 Sp4 基因在齿状回空泡化中的细胞自主作用，以及感觉运动门控和情境记忆的相关缺陷。将通过内部核糖体进入位点将诱导型 cre-ERT2 基因融合到内源桥粒蛋白 (Dsp) 基因的 3' UTR 内，而不敲除 Dsp 表达，从而创建小鼠品系。他莫昔芬将用于激活 ere，从而重新激活或消除齿状颗粒细胞中的 Sp4 表达。将在这些救援或条件性基因敲除小鼠中评估海马结构和功能异常。具体目标 2 将确定海马体中 Sp4 介导的遗传通路，这些通路有助于新物体探索。研究将 (a) 进一步分析亚效型 Sp4 小鼠在既定范式中的有缺陷的新颖性探索； (b) 检查齿状颗粒细胞中 Sp4 表达的恢复或消除（目标 1）是否可以挽救或导致有缺陷的新奇反应。具体目标 3 将使用药理学和遗传学方法研究 Grk4 介导的信号通路在 Sp4 低效小鼠感觉运动门控调节中的作用。细胞培养实验将检查 Sp4 突变海马细胞中 Grk4 介导的多巴胺 D1 和 mGluRI 受体的脱敏作用。多巴胺 D1 和 mGluRI 受体的拮抗剂将被给予亚效型 Sp4 突变小鼠，以测试前脉冲抑制缺陷的逆转。为了评估 Grk4 介导的 GPCR 信号通路在感觉运动门控和海马空泡化调节中的破坏，将产生将 Sp4 缺失与多巴胺 D1 或 mGluRI 受体基因相结合的双敲除小鼠。这些实验将对海马体内的遗传途径产生新的见解，这些遗传途径是与几种精神疾病相关的行为异常的基础。