Department of Psychiatry, University of Pennsylvania, Philadelphia, USA; Department of Child and Adolescent Psychiatry, Children's Hospital of Philadelphia, Philadelphia, USA.
Department of Psychiatry, University of Pennsylvania, Philadelphia, USA; Department of Psychiatry and Behavioral Sciences, University of California, Los Angeles, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jul 13;93:84-92. doi: 10.1016/j.pnpbp.2019.02.017. Epub 2019 Feb 28.
Much evidence suggests that hypofunction of the N-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 Src Acl gene (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.
大量证据表明，N-甲基-D-天冬氨酸谷氨酸受体（NMDAR）功能低下可能广泛导致精神疾病和发育障碍中常见的分子、认知和行为异常的一个亚群。然而，对于导致 NMDAR 功能障碍的特定分子变化知之甚少。因此，基于特定病因学，针对 NMDAR 功能障碍进行个性化治疗的方法仍然是一个挑战。肉瘤酪氨酸激酶（Src）作为影响 GluN2 磷酸化的多种信号机制的枢纽，并且可以被各种信号通路的会聚改变所破坏。我们最近发现，尽管精神分裂症患者死后组织中 MK-801 结合和 NMDA 受体复合物表达增加，但 Src 信号减少。这些数据表明，Src 失调可能是导致谷氨酸信号减少的重要潜在机制。尽管有证据表明 Src 在 NMDAR 信号中起核心作用，但对于 Src 活性降低如何调节认知和行为的表型变化知之甚少。因此，目前的研究旨在表征 Src Acl 基因杂合子（Src+/- 小鼠）的小鼠的行为和电生理表型。与 Src+/+（WT）小鼠相比，Src+/- 小鼠表现出社交能力和工作记忆减少，而在运动活性和焦虑相关行为方面没有显著差异。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）幅度降低、失匹配负波（MMN）降低和诱发伽马功率降低，而雄性小鼠仅表现出这些改变。这些数据表明，Src+/- 小鼠是一种很有前途的新模型，可以帮助理解这些电生理、行为和认知变化的病理生理学。因此，我们提出 Src+/- 小鼠可以用于未来通过靶向增加 Src 活性作为精神分裂症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来评估潜在的治疗方法。
