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: 8117018
• 负责人: XIANJIN ZHOU
• 金额: $ 38.25万
• 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/8117018
• 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为我们对大脑疾病的理解做出巨大贡献。Sp4转录因子表达减少的突变小鼠在感觉运动门控和上下文学习方面表现出缺陷，这与假定的精神分裂症内表型相似。Sp4基因与精神分裂症和双相情感障碍显著相关。在小鼠研究中，Sp4基因的表达减少会损害海马CA1的长期增强（LTP），损害空间学习，并显著降低NMDA谷氨酸受体核心亚基NMDAR1的表达。NMDA功能受损在精神分裂症的病理生理中起着核心作用。Sp4-NMDAR1通路的发现为人类精神疾病的跨物种研究提供了基础。这项更新应用研究了Sp4如何调节NMDAR1蛋白的表达来调节涉及感觉运动门控和认知功能的神经通路。主要假设是Sp4转录后调控NMDAR1的表达，恢复Sp4-NMDAR1在特定大脑区域的表达将逆转Sp4半形小鼠的感觉运动门控和认知缺陷。四个特定目标将验证这些假设：目标1：阐明NMDAR1蛋白在野生型和Sp4亚型小鼠之间差异表达的分子机制。NMDAR1 mRNA的定位将通过原位杂交检测。NMDAR1蛋白的差异翻译和转换将使用TimeSTAMP2.2-Venus标签进行检测。目的2：通过恢复兴奋性神经元和抑制性神经元中Sp4-NMDAR1的表达来逆转感觉运动门控缺陷。Sp4- nmdar1在新皮层和海马的兴奋性和抑制性神经元中的表达将得到恢复，从而逆转Sp4亚型小鼠的脉冲前抑制门控缺陷。分子和药理学研究将进一步表征条件获救小鼠。目的3：确定Sp4半形小鼠是否表现出由额叶皮质调节的认知缺陷，以及恢复额叶皮质中Sp4- nr1的表达是否会逆转这些缺陷。注意-设置转移任务和气味跨度任务将被用来检测Sp4拟态和条件获救小鼠的认知功能。目的4：检验恢复海马CA1中Sp4的表达是否足以逆转Sp4亚型的LTP和空间学习缺陷。通过与CamK2a-Cre和Sp4亚型小鼠杂交，可以恢复CA1中Sp4- NMDAR1的表达。我们将在携带CamK2a-Cre的Sp4拟态小鼠中研究空间和情境记忆的形成和巩固。本研究将有助于阐明感觉运动门控和学习调节的分子机制，并有助于制定预防人类精神疾病Sp4-NMDAR1通路下调的临床干预措施。