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: 9312317
• 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/9312317
• 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; Clinical; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Complex; Data; Development; Disease; Dopamine D2 Receptor; Electrophysiology (science); Etiology; Evolution; Exhibits; FRAP1 gene; Frequencies; Functional disorder; Genes; Genetic; Genetic Variation; Genetic study; Hippocampus (Brain); Homeostasis; Human; IC 87114; Immunoassay; Impaired cognition; Impairment; 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; Pharmacology; Phase; Phenotype; Physiological Processes; Play; Property; Protein Isoforms; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Psychiatric therapeutic procedure; Regimen; Regulation; Risk; Rodent Model; Role; Schizophrenia; Signal Transduction; Slice; Synapses; Synaptic Transmission; System; Testing; Therapeutic; Transgenic Mice; Treatment outcome; Work; base; behavioral response; brain abnormalities; cell growth; cognitive development; cognitive enhancement; cognitive function; cognitive process; defined contribution; drug development; experimental study; 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; public health relevance; 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）是一种以认知功能障碍为特征的复杂遗传神经发育障碍。认知缺陷的病因学基础尚不清楚，但证据详细说明了AKT信号和神经元/突触稳态调节基因的异常，强调了高级精神药物开发的靶标途径。人类和小鼠的遗传研究表明，AKT1与SZ、前额皮质（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，最近的SZ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。