Sp4 Pathway in the Modulation of Sensorimotor Gating and Memory

Sp4 通路在感觉运动门控和记忆调节中的作用

• 批准号: 8488881
• 负责人: XIANJIN ZHOU
• 金额: $ 8.88万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8488881
• 关键词: Abbreviations; Affect; Animal Model; Animals; Bipolar Disorder; Brain; Brain Diseases; Brain region; California; Clinical; Code; Cognitive; Cognitive deficits; Dependovirus; Development; Down-Regulation; Encephalitis; Exhibits; Foundations; Functional disorder; Generations; Genes; Genetic; Glutamate Receptor; Glutamates; Hippocampus (Brain); Human; Human Genetics; Impaired cognition; In Situ Hybridization; Intervention; Learning; Long-Term Potentiation; Measures; Memory; Memory impairment; Mental disorders; Messenger RNA; Modeling; Molecular; Molecular Probes; Mus; Mutant Strains Mice; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor A1; Neocortex; Neural Pathways; Odors; Pathway interactions; Patients; Phencyclidine; Play; Progress Reports; Proteins; RNA; Role; Schizophrenia; Short-Term Memory; Solid; Sp4 transcription factor; Susceptibility Gene; Symptoms; Syndrome; Testing; Translations; Venus; Work; base; brain cell; cognitive function; dentate gyrus; endophenotype; excitatory neuron; executive function; frontal lobe; genetic manipulation; inhibitory neuron; neurotransmission; novel; postnatal; prepulse inhibition; prevent; public health relevance; receptor; restoration; transcription factor

DESCRIPTION (provided by applicant): Animal models based on genetic manipulations can contribute enormously to our understanding of diseases of the brain. Mutant mice with reduced expression of the Sp4 transcription factor display deficits in sensorimotor gating and contextual learning that resemble putative endophenotypes for schizophrenia. The Sp4 gene is significantly associated with schizophrenia and bipolar disorder. In mouse studies, reduced expression of the Sp4 gene impaired long-term potentiation (LTP) in hippocampal CA1, impaired spatial learning, and markedly decreased the expression of NMDAR1, the core subunit for NMDA glutamate receptors. Impaired NMDA function plays a central role in the pathophysiology of schizophrenia. This identification of a novel Sp4-NMDAR1 pathway provides a basis for cross-species studies related to human psychiatric disorders. This renewal application investigates how Sp4 regulates expression of NMDAR1 proteins to modulate neural pathways involved in sensorimotor gating and cognitive functions. The central hypotheses are that Sp4 post-transcriptionally regulates the expression of NMDAR1 and that restoration of Sp4-NMDAR1 expression in specific brain regions will reverse both sensorimotor gating and cognitive deficits in Sp4 hypomorphic mice. Four Specific Aims will test these hypotheses: Aim 1: To elucidate molecular mechanisms for differential expression of NMDAR1 proteins between wildtype and Sp4 hypomorphic mice. The localization of NMDAR1 mRNA will be examined by in situ hybridization. The differential translation and turnover of NMDAR1 proteins will be examined using TimeSTAMP2.2-Venus tag. Aim 2: To reverse deficient sensorimotor gating by restoring Sp4-NMDAR1 expression in excitatory and inhibitory neurons respectively. The expression of Sp4-NMDAR1 will be restored in excitatory and inhibitory neurons of both neocortex and hippocampus, to reverse prepulse inhibition gating deficits in Sp4 hypomorphic mice. Molecular and pharmacological studies will further characterize the conditional rescued mice. Aim 3: To determine whether Sp4 hypomorphic mice exhibit cognitive deficits modulated by the frontal cortex, and whether restoration of Sp4-NR1 expression in frontal cortex will reverse these deficits. Both the Attentional-Set-Shifting Task and the Odor Span Task will be used to examine cognitive functions in Sp4 hypomorphic and conditional rescued mice. Aim 4: To test whether restoration of Sp4 expression in hippocampal CA1 is sufficient to reverse the LTP and spatial learning deficits in Sp4 hypomorphs. Sp4- NMDAR1 expression will be restored in CA1 by crossing CamK2a-Cre and Sp4 hypomorphic mice. The formation and consolidation of spatial and contextual memories will be examined in the Sp4 hypomorphic mice harboring CamK2a-Cre. The proposed studies will help elucidate molecular mechanisms underlying the modulation of sensorimotor gating and learning, and aid the development of clinical interventions to prevent the down-regulation of Sp4-NMDAR1 pathway in human psychiatric disorders. PUBLIC HEALTH RELEVANCE: The Sp4 gene, which has recently been associated with both schizophrenia and bipolar disorder, codes for an important transcription factor in brain cells that regulates the function of glutamatergic receptors involved in the cognitive impairments in psychiatric disorders. This project seeks to use animal models to elucidate molecular mechanisms related to specific cognitive abnormalities in schizophrenia, in order to aid the development of clinical interventions to prevent the dysregulation of the Sp4-glutamate pathway in human psychiatric disorders.

描述（由申请人提供）：基于基因操作的动物模型可以极大地促进我们对大脑疾病的理解。 Sp4转录因子表达减少的突变小鼠表现出感觉运动门控和情境学习方面的缺陷，类似于精神分裂症的假定内表型。 Sp4基因与精神分裂症和双相情感障碍显着相关。在小鼠研究中，Sp4 基因表达的减少会损害海马 CA1 的长时程增强 (LTP)，损害空间学习，并显着降低 NMDAR1（NMDA 谷氨酸受体的核心亚基）的表达。 NMDA 功能受损在精神分裂症的病理生理学中发挥着核心作用。新型 Sp4-NMDAR1 通路的鉴定为与人类精神疾病相关的跨物种研究奠定了基础。该更新应用研究了 Sp4 如何调节 NMDAR1 蛋白的表达，从而调节涉及感觉运动门控和认知功能的神经通路。中心假设是 Sp4 转录后调节 NMDAR1 的表达，并且特定大脑区域中 Sp4-NMDAR1 表达的恢复将逆转 Sp4 低效小鼠的感觉运动门控和认知缺陷。四个具体目标将检验这些假设： 目标 1：阐明野生型和 Sp4 亚效型小鼠之间 NMDAR1 蛋白差异表达的分子机制。 NMDAR1 mRNA 的定位将通过原位杂交进行检查。将使用 TimeSTAMP2.2-Venus 标签检查 NMDAR1 蛋白的差异翻译和周转。目标 2：通过分别恢复兴奋性和抑制性神经元中 Sp4-NMDAR1 的表达来逆转感觉运动门控缺陷。 Sp4-NMDAR1 的表达将在新皮质和海马的兴奋性和抑制性神经元中恢复，以逆转 Sp4 低效小鼠的前脉冲抑制门控缺陷。分子和药理学研究将进一步表征有条件获救的小鼠。目标 3：确定 Sp4 低效小鼠是否表现出由额叶皮层调节的认知缺陷，以及额叶皮层 Sp4-NR1 表达的恢复是否会逆转这些缺陷。注意力组转移任务和气味广度任务都将用于检查 Sp4 低形态和有条件获救小鼠的认知功能。目标 4：测试海马 CA1 中 Sp4 表达的恢复是否足以逆转 Sp4 亚型的 LTP 和空间学习缺陷。通过 CamK2a-Cre 和 Sp4 低等态小鼠杂交，CA1 中 Sp4-NMDAR1 表达将恢复。将在携带 CamK2a-Cre 的 Sp4 低等态小鼠中检查空间和情境记忆的形成和巩固。拟议的研究将有助于阐明感觉运动门控和学习调节的分子机制，并有助于开发临床干预措施，以防止人类精神疾病中 Sp4-NMDAR1 通路的下调。 公共健康相关性：Sp4 基因最近被发现与精神分裂症和双相情感障碍有关，它编码脑细胞中的一种重要转录因子，调节与精神疾病认知障碍有关的谷氨酸能受体的功能。该项目旨在利用动物模型来阐明与精神分裂症特定认知异常相关的分子机制，以帮助开发临床干预措施，以防止人类精神疾病中 Sp4-谷氨酸途径的失调。