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: 7984812
• 负责人: XIANJIN ZHOU
• 金额: $ 38.63万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7984812
• 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; NR1 NMDA receptor; NR1 gene; 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; 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）：基于遗传操作的动物模型可以极大地有助于我们对大脑疾病的理解。 SP4转录因子表达降低的突变小鼠在感觉运动门控和上下文学习中表现出类似于精神分裂症的假定内型型的缺陷。 SP4基因与精神分裂症和躁郁症显着相关。在小鼠研究中，SP4基因在海马CA1中的长期增强（LTP）的表达降低，空间学习受损，并显着降低了NMDAR1的表达，NMDAR1是NMDA谷氨酸受体的核心亚基。 NMDA功能受损在精神分裂症的病理生理中起着核心作用。新型SP4-NMDAR1途径的这种识别为与人类精神疾病有关的跨物种研究提供了基础。该更新应用研究了SP4如何调节NMDAR1蛋白的表达，以调节与感觉运动门控和认知功能有关的神经途径。中心假设是，转录后SP4调节NMDAR1的表达，并且在特定大脑区域中SP4-NMDAR1表达的恢复会逆转SP4型型型型型小鼠中的感觉运动门控和认知缺陷。四个具体目的将检验以下假设：目标1：阐明野生型和SP4型型型型肌蛋白之间NMDAR1蛋白差异表达的分子机制。 NMDAR1 mRNA的定位将通过原位杂交检查。 NMDAR1蛋白的差分翻译和周转率将使用Timestamp2.2-Venus标签进行检查。目标2：通过分别在兴奋性和抑制性神经元中恢复SP4-NMDAR1的表达来逆转不足的感觉运动门控。 SP4-NMDAR1的表达将在新皮层和海马的兴奋性和抑制性神经元中恢复，以逆转SP4型型型型型肌硫酸小鼠的抑制抑制缺陷。分子和药理学研究将进一步表征有条件的救出小鼠。 AIM 3：确定SP4型肌型小鼠是否表现出由额叶皮层调节的认知缺陷，以及额叶皮质中SP4-NR1表达的恢复是否会逆转这些缺陷。注意设定的转移任务和气味跨度任务均应用于检查SP4型肌电和条件救出的小鼠的认知功能。 AIM 4：测试海马CA1中SP4表达的恢复是否足以扭转SP4 hypomorphs中的LTP和空间学习缺陷。 SP4-NMDAR1表达将在CA1中恢复CAMK2A-CRE和SP4型肌型小鼠。将在带有CAMK2A-CRE的SP4型肌型小鼠中检查空间和上下文记忆的形成和整合。拟议的研究将有助于阐明感觉运动门控和学习调节的基础的分子机制，并有助于开发临床干预措施，以防止人类精神疾病中SP4-NMDAR1途径的下调。 公共卫生相关性：最近与精神分裂症和双相情感障碍相关的SP4基因编码脑细胞中重要的转录因子，该转录因子调节谷氨酸能受体在精神疾病中涉及认知障碍的功能。该项目试图使用动物模型来阐明与精神分裂症特异性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。