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。

基本信息

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
项目类别：
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

项目摘要

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（由申请人证明）：精神分裂症（SZ）是一种遗传性的，神经发育障碍，通过认知为isus isus的病态学基础，不清楚神经元/突触稳态的离子，突出显示具有先进精神发展风险的神经元/突触稳态。 SZ中的皮质（PFC）和海马功能和学习中的缺陷。 Akt信号的神经生物学机制仍然是复杂的，涉及I独立基因的三个同源性成员（Akt1，Akt2和Akt3），每个基因都在细胞生长，代谢和生存中发挥不同的作用。在与神经元发育和功能相关的生理学过程中，各个AKT的脑部作用和整个途径是认知和精神疾病，是多巴胺D2受体拮抗剂UGS的差异，增强了Vivo中的Akt活性当前的神经疗法无法在疾病中信任认知功能障碍。在此提案中。测试电池，我们将检查p110（利用IC87114）M是否可以改善与与同工型特异性AKT相关的Akt1 y相关的PFC依赖性认知。 l理解SZ病理生理学并正在治疗的框架。