Targets for treating schizophrenia: AKT in neurodevelopment and cognition.

描述(申请人提供)：精神分裂症(SZ)是一种复杂的遗传性神经发育障碍，以认知功能障碍为特征。认知障碍的病因学基础尚不清楚，但有证据表明，聚集在AKT信号和神经元/突触稳态调节上的基因异常，突显了先进精神药物开发的靶向途径。对人类和小鼠的遗传学研究表明，AKT1与SZ、前额叶皮质(PFC)和海马区功能异常以及学习、记忆和注意力缺陷的风险有关。此外，最近在SZ的全基因组关联数据强调了AKT3基因的遗传变异在风险中的重要作用。 其神经生物学机制尚不清楚。AKT信号的生物学是复杂的，涉及三个同源成员(AKT1、AKT2和AKT3)，它们由独立的基因编码，每个成员在细胞生长、代谢和生存中扮演着不同的、功能上相互关联的角色。尽管所有AKT亚型都在脑内高表达，AKT3突变与脑发育异常有关，AKT信号在SZ中缺乏，但单个AKT及其通路作为一个整体在与神经元发育和功能、认知和精神疾病相关的生理过程中的机制作用尚不清楚。此外，多巴胺D2受体拮抗剂作为临床上主要有效的抗精神病药物，在体内可增强AKT活性，提示与治疗作用相关的分子机制。然而，目前尚不清楚哪些同工型是靶向，也不清楚为什么目前的抗精神病药物未能治疗这种疾病的认知功能障碍。相应地，我们最近的工作发现，通过选择性药物调节PI3Kinase p110�(与IC87114)增强AKT通路，在SZ啮齿动物模型中具有抗精神病特性。值得注意的是，我们的初步数据扩展了这一点，表明该药物具有增强认知的好处。这些数据表明，AKT信号的直接、药理学增强可能代表着治疗SZ认知功能障碍的一种改进的治疗方法。在这项提案中，我们将使用Akt1、Akt2和AKT3单一基因缺失的小鼠，利用全细胞体外切片电生理学和蛋白质组学方法，确定AKT同种类型在皮质回路发育中的机制作用。我们还将使用小鼠临床前神经认知测试组件，确定每种AKT亚型对认知和行为发育的贡献，因为它与SZ有关。最后，我们将研究p110AKT抑制(利用IC87114)是否是一种有效的机制来改善与Akt1、Akt2或Akt3缺陷相关的�依赖的认知缺陷，并确定积极的结果如何与同型特异性AKT信号机制相关。总体而言，这些研究将为了解单个Akt亚型的神经生物学作用提供重要的见解，并直接影响基于PI3K/AKT的治疗方案在治疗SZ认知缺陷方面的潜在使用，为理解SZ的病理生理及其治疗提供重要的翻译框架。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a complex genetic, neurodevelopmental disorder characterized by cognitive dysfunction. The etiological basis of cognitive deficits is unclear, but evidence details abnormalities in genes that converge on AKT signaling and the regulation of neuronal/synaptic homeostasis, highlighting a target pathway for advanced psychiatric drug development. Genetic studies in humans and mice demonstrate that AKT1 is associated with risk for SZ, abnormal prefrontal cortical (PFC) and hippocampal function and deficits in learning, memory and attention. Furthermore, recent genome-wide association data in SZ highlight a significant role for genetic variation in the AKT3 gene in risk. The neurobiological mechanisms remain unknown. The biology of AKT signaling is complex, involving three homologous members (AKT1, AKT2, and AKT3), encoded by independent genes, each playing distinct and functionally interrelated roles in cell growth, metabolism and survival. Despite the knowledge that all AKT isoforms are highly expressed in brain, AKT3 mutations are linked to abnormal brain development, and AKT signaling is deficient in SZ, the mechanistic role of the individual AKTs and the pathway as a whole in physiological processes relevant to neuronal development and function, cognition and psychiatric illness, is poorly understood. Moreover, dopamine D2 receptor antagonists, the main clinically effective antipsychotic drugs, enhance AKT activity in vivo, suggesting a molecular mechanism relevant to therapeutic action. However, it is unclear which isotypes are targeted and why current neuroleptics fail to treat cognitive dysfunction in the disorder. Relevantly, our recent work has identified that enhancement of the AKT pathway via selective pharmacological modulation of the PI3Kinase, p110�(with IC87114), has antipsychotic properties in rodent models of SZ. Significantly, our preliminary data extend this to show that the drug has cognitive enhancing benefits. These data suggest that direct, pharmacological enhancement of AKT signaling may represent a refined therapeutic approach to treating cognitive dysfunction in SZ. In this proposal we will use mice with single genetic deletions of Akt1, Akt2 and Akt3 to determine the mechanistic role of AKT isotypes in cortical circuit development, using whole-cell in-vitro slice electrophysiology and proteomic approaches. We will also define the contribution of each AKT isoform to cognitive and behavioral development as it relates to SZ using a murine preclinical neurocognitive test battery. Finally, we will examine whether p110�nhibition (utilizing IC87114) is an effective mechanism to improve PFC-dependent cognitive deficits associated with Akt1, Akt2 or Akt3 deficiency and determine how positive outcomes are mechanistically related to isoform-specific AKT signaling. Overall these studies will provide important insight into the neurobiological roles of individual Akt isotypes and directly impact the potential use of PI3K/AKT-based therapeutic regimens for treating cognitive deficits in SZ, providing an important translational framework for understanding SZ pathophysiology and its treatment.