Targets for treating schizophrenia: AKT in neurodevelopment and cognition.

治疗精神分裂症的目标：神经发育和认知中的 AKT。

• 批准号: 9130264
• 负责人: Amanda Jayne Law
• 金额: $ 41.99万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-12 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130264
• 关键词: AKT Signaling Pathway; AKT1 gene; AKT2 gene; AKT3 gene; ARHGEF5 gene; Affect; Antipsychotic Agents; Attention; Behavior; Behavioral; Biochemical; Biological; Biology; Brain; Cells; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Complex; Data; Development; Disease; Dopamine D2 Receptor; Electrophysiology (science); Evolution; Exhibits; FRAP1 gene; Frequencies; Functional disorder; Genes; Genetic; Genetic Variation; Genetic study; Health; Hippocampus (Brain); Homeostasis; Human; IC 87114; Immunoassay; Impaired cognition; In Vitro; Individual; Knowledge; Learning; Link; MAP Kinase Gene; Mediating; Memory; Mental disorders; Metabolism; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Neuregulin 1; Neurobiology; Neurodevelopmental Disorder; Neurons; Outcome; PI3K/AKT; Pathway interactions; Pharmaceutical Preparations; Phase; Phenotype; Physiological Processes; Play; Property; Protein Isoforms; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Regimen; Regulation; Risk; Rodent Model; Role; Schizophrenia; Signal Transduction; Slice; Synapses; Synaptic Transmission; System; Testing; Therapeutic; Transgenic Mice; Treatment outcome; Work; base; behavioral response; cell growth; cognitive development; cognitive function; cognitive process; defined contribution; drug development; genome wide association study; improved; in vivo; inhibitor/antagonist; insight; member; mouse model; neural circuit; neurobiological mechanism; neurocognitive test; neurodevelopment; neuron development; new therapeutic target; novel; postnatal; pre-clinical; research study; risk variant

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.

描述（由申请人提供）：精神分裂症（SZ）是一种复杂的遗传性神经发育障碍，其特征是认知功能障碍。认知缺陷的病因学基础尚不清楚，但证据详细说明了聚集在AKT信号传导和神经元/突触稳态调节上的基因异常，突出了高级精神药物开发的靶向途径。人类和小鼠的遗传研究表明，AKT 1与SZ、前额叶皮质（PFC）和海马功能异常以及学习、记忆和注意力缺陷的风险相关。此外，最近SZ的全基因组关联数据突出了AKT 3基因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信号传导的生物学是复杂的，涉及三个同源成员（AKT 1，AKT 2和AKT 3），由独立的基因编码，每个在细胞生长，代谢和存活中发挥独特的和功能相关的作用。尽管知道所有AKT同种型在脑中高度表达，AKT 3突变与异常脑发育有关，并且SZ中AKT信号传导缺乏，但对单个AKT和整个通路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知之甚少。此外，多巴胺D2受体拮抗剂，主要的临床有效的抗精神病药物，提高AKT活性在体内，这表明相关的治疗作用的分子机制。然而，目前还不清楚哪些同种型是靶向的，以及为什么目前的神经阻滞剂不能治疗这种疾病的认知功能障碍。与此相关的是，我们最近的工作已经确定，通过选择性药理学调节PI 3激酶p110 β（与IC 87114）来增强AKT通路，在SZ的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益处。这些数据表明，AKT信号的直接药理学增强可能代表了治疗SZ认知功能障碍的精细治疗方法。在这个提议中，我们将使用Akt 1，Akt 2和Akt 3的单一基因缺失的小鼠，以确定AKT同种型在皮质回路发育中的机制作用，使用全细胞体外切片电生理学和蛋白质组学方法。我们还将使用小鼠临床前神经认知测试组合来定义每个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p110抑制剂（利用IC 87114）是否是改善与Akt 1，Akt 2或Akt 3缺陷相关的PFC依赖性认知缺陷的有效机制，并确定积极结果如何与亚型特异性AKT信号传导机制相关。总体而言，这些研究将提供重要的洞察个体Akt同种型的神经生物学作用，并直接影响基于PI 3 K/AKT的治疗方案用于治疗SZ认知缺陷的潜在用途，为理解SZ病理生理学及其治疗提供重要的翻译框架。