Src hypoactivity as a mediator of various molecular alterations leading to NMDAR

Src 活性低下作为导致 NMDAR 的各种分子改变的介质

• 批准号: 10054787
• 负责人: Karin Borgmann-Winter
• 金额: $ 21.49万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-11-12 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054787
• 关键词: Src; hypoactivity; mediator; various; molecular

 DESCRIPTION (provided by applicant): The N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis is one of the leading postulates for the pathophysiology of schizophrenia (SCZ) and is supported by numerous pharmacologic, behavioral and genetic studies. Nevertheless, we have little insight into specific alterations in NMDAR signaling and its mechanistic basis in SCZ patients. This is a critical knowledge gap, which has impeded further development of this hypothesis and limited our efforts to identify specific therapeutic interventions. (Preliminary Data) As direct evidence for altered NMDA receptor (NMDAR) signaling, we found decreased NMDA/Glycine induced tyrosine phosphorylation of NMDAR subunit 2 (GluN2) and reduced downstream signaling in the postmortem dorsal lateral prefrontal cortex (DLPFC) of SCZ cases. These changes are not associated with decreased NMDARs but with reduced activity of a cascade of kinases- Src kinase, protein kinase C and Pyk2- which in concert decrease GluN2 tyrosine phosphorylation. We found multiple molecular alterations in the DLPFC of SCZ cases; increased PSD-95, increased erbB4 activity, decreased dysbindin -1 and RPTPa, each of which can induce Src hypoactivity. (Hypotheses) We hypothesize that hypoactivity of Src in the NMDAR complex (Src-NR) reduces GluN tyrosine phosphorylation and is caused by altered protein interactions in a network of Src-NR-associated proteins ( the Src-NR interactome), which can be leveraged to modify behavioral phenotypes of NMDAR hypoactivity. (Approach) We propose a human-rodent translation strategy, by which we analyze disease related alterations in postmortem brains and examine their underlying mechanisms in rodent studies. Aim 1 will further examine postmortem brains of an elderly and mid-life SCZ cohorts to identify molecular alterations in the Src-NR interactome in SCZ, Aim 2 will determine the role of protein interactions in Src-NR hypoactivity and test rescue strategies in ex vivo preparations of rodent and human postmortem tissues and Aim 3 will determine SCZ related behavior and EEG phenotypes of Src-/- mice and test if Src enhancement can rescue such phenotypes in vivo.

 描述（由申请人提供）：N-甲基-D-天冬氨酸（NMDA）受体功能减退假说是精神分裂症（SCZ）病理生理学的主要假说之一，并得到大量药理学、行为和遗传学研究的支持。然而，我们对 SCZ 患者 NMDAR 信号传导的具体改变及其机制基础知之甚少。这是一个关键的知识差距，阻碍了这一假设的进一步发展，并限制了我们确定具体治疗干预措施的努力。 （初步数据）作为 NMDA 受体 (NMDAR) 信号传导改变的直接证据，我们发现 NMDA/甘氨酸诱导的 NMDAR 亚基 2 (GluN2) 酪氨酸磷酸化减少，并且 SCZ 病例死后背外侧前额皮质 (DLPFC) 中下游信号传导减少。这些变化与 NMDAR 的减少无关，而是与一系列激酶（Src 激酶、蛋白激酶 C 和 Pyk2）活性的降低有关，这会共同降低 GluN2 酪氨酸磷酸化。我们在 SCZ 病例的 DLPFC 中发现了多种分子改变； PSD-95 增加、erbB4 活性增加、dysbindin -1 和 RPTPa 减少，其中每一个都会导致 Src 活性低下。 （假设）我们假设 NMDAR 复合物 (Src-NR) 中的 Src 活性低下会降低 GluN 酪氨酸磷酸化，并且是由 Src-NR 相关蛋白网络（Src-NR 相互作用组）中的蛋白质相互作用改变引起的，可以利用该蛋白相互作用来改变 NMDAR 活性低下的行为表型。 （方法）我们提出了一种人类-啮齿动物翻译策略，通过该策略我们分析死后大脑中与疾病相关的变化，并在啮齿动物研究中检查其潜在机制。目标 1 将进一步检查老年和中年 SCZ 队列的死后大脑，以确定 SCZ 中 Src-NR 相互作用组的分子变化，目标 2 将确定蛋白质相互作用在 Src-NR 低活性中的作用，并在啮齿动物和人类死后组织的离体制备中测试救援策略，目标 3 将确定 Src-/- 小鼠的 SCZ 相关行为和 EEG 表型，并测试是否 Src 增强可以在体内挽救此类表型。

项目成果

Sensory processing in autism spectrum disorders and Fragile X syndrome-From the clinic to animal models.

• DOI: 10.1016/j.neubiorev.2016.05.029
• 发表时间: 2017-05
• 期刊: Neuroscience and biobehavioral reviews
• 影响因子: 8.2
• 作者: Sinclair D;Oranje B;Razak KA;Siegel SJ;Schmid S
• 通讯作者: Schmid S

Cellular and circuit models of increased resting-state network gamma activity in schizophrenia.

• DOI: 10.1016/j.neuroscience.2015.11.011
• 发表时间: 2016-05-03
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: White RS;Siegel SJ
• 通讯作者: Siegel SJ

Src deficient mice demonstrate behavioral and electrophysiological alterations relevant to psychiatric and developmental disease.

Src 缺陷小鼠表现出与精神和发育疾病相关的行为和电生理改变。

• DOI: 10.1016/j.pnpbp.2019.02.017
• 发表时间: 2019
• 期刊: Progress in neuro-psychopharmacology & biological psychiatry
• 影响因子: 5.6
• 作者: Ward,KatelynR;Featherstone,RobertE;Naschek,MelissaJ;Melnychenko,Olga;Banerjee,Anamika;Yi,Janice;Gifford,RaymondL;Borgmann-Winter,KarinE;Salter,MichaelW;Hahn,Chang-Gyu;Siegel,StevenJ
• 通讯作者: Siegel,StevenJ

Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus.

• DOI: 10.1186/s11689-016-9148-7
• 发表时间: 2016
• 期刊: Journal of neurodevelopmental disorders
• 影响因子: 4.9
• 作者: Sinclair D;Cesare J;McMullen M;Carlson GC;Hahn CG;Borgmann-Winter KE
• 通讯作者: Borgmann-Winter KE

Ceftriaxone reverses ketamine-induced lasting EEG and astrocyte alterations in juvenile mice.

• DOI: 10.1016/j.drugalcdep.2015.07.1198
• 发表时间: 2015-11-01
• 期刊: Drug and alcohol dependence
• 影响因子: 4.2
• 作者: Dodman K;Featherstone RE;Bang J;Liang Y;Siegel SJ
• 通讯作者: Siegel SJ