Src deficient mice demonstrate behavioral and electrophysiological alterations relevant to psychiatric and developmental disease.
Src deficient mice demonstrate behavioral and electrophysiological alterations relevant to psychiatric and developmental disease.
复制标题
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
复制
发表时间：
2019
影响因子：
5.6
通讯作者：
Siegel,StevenJ
中科院分区：
文献类型：
--
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
大量证据表明，N-甲基-D-天冬氨酸谷氨酸受体（NMDAR）功能低下可能广泛地导致精神和发育疾病中常见的分子、认知和行为异常。然而，我们对导致NMDAR功能障碍的特定分子变化知之甚少。因此，基于特定病因来补救NMDAR功能障碍的个性化方法仍然是一个挑战。肉瘤酪氨酸激酶（Src）作为影响GluN 2磷酸化的多种信号传导机制的枢纽，并且可以被各种信号传导途径的会聚改变破坏。我们最近发现，尽管MK-801结合和NMDA受体复合物在突触后密度（PSD）中的表达增加，但精神分裂症患者死后组织中Src信号传导减少。这些数据表明，Src失调可能是一个重要的潜在机制，负责减少谷氨酸信号。尽管有证据表明Src在NMDAR信号传导中起着重要作用，但关于Src活性的降低如何调节认知和行为的表型变化却知之甚少。因此，目前的研究试图表征SrcAcl基因杂合子小鼠（Src+/−小鼠）的行为和电生理表型。Src+/−小鼠表现出相对于Src+/+（WT）小鼠的社交能力和工作记忆下降，而在运动活动和焦虑相关行为方面没有观察到显著差异。与WT小鼠相比，Src+/−小鼠表现出中潜伏期P20听觉事件相关电位（aERP）振幅降低、失配负波（MMN）降低和诱发伽马功率降低，仅在雄性中存在。这些数据表明Src+/-小鼠是一种很有前途的新模型，可以帮助了解这些电生理、行为和认知变化的病理生理学。因此，我们建议Src+/−小鼠可以在未来用于评估潜在的治疗方法，通过靶向增加Src活性作为SCZ和其他以谷氨酸功能降低为特征的疾病的多种病因的共同最终途径。
Much evidence suggests that hypofunction of theN-methyl-d-aspartate glutamate receptor (NMDAR) may contribute broadly towards a subset of molecular, cognitive and behavioral abnormalities common among psychiatric and developmental diseases. However, little is known about the specific molecular changes that lead to NMDAR dysfunction. As such, personalized approaches to remediating NMDAR dysfunction based on a specific etiology remains a challenge. Sarcoma tyrosine kinase (Src) serves as a hub for multiple signaling mechanisms affecting GluN2 phosphorylation and can be disrupted by convergent alterations of various signaling pathways. We recently showed reduced Src signaling in post mortem tissue from schizophrenia patients, despite increased MK-801 binding and NMDA receptor complex expression in the postsynaptic density (PSD). These data suggest that Src dysregulation may be an important underlying mechanism responsible for reduced glutamate signaling. Despite this evidence for a central role of Src in NMDAR signaling, little is known about how reductions in Src activity might regulate phenotypic changes in cognition and behavior. As such, the current study sought to characterize behavioral and electrophysiological phenotypes in mice heterozygous for the SrcAclgene (Src+/− mice). Src+/− mice demonstrated decreased sociability and working memory relative to Src+/+ (WT) mice while no significant differences were seen on locomotive activity and anxiety-related behavior. In relation to WT mice, Src+/− mice showed decreased mid-latency P20 auditory event related potential (aERP) amplitudes, decreased mismatch negativity (MMN) and decreased evoked gamma power, which was only present in males. These data indicate that Src+/− mice are a promising new model to help understand the pathophysiology of these electrophysiological, behavioral and cognitive changes. As such, we propose that Src+/− mice can be used in the future to evaluate potential therapeutic approaches by targeting increased Src activity as a common final pathway for multiple etiologies of SCZ and other diseases characterized by reduced glutamate function.