Improving cortical function & cognition in schizophrenia by modulation of mGluR5

改善皮质功能

• 批准号: 8815002
• 负责人: JAMES M MCNALLY
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815002
• 关键词: Accounting; Acoustic Stimulation; Acute; Address; Affect; Age; Agonist; Animals; Antipsychotic Agents; Appearance; Area; Attention; Auditory; Autopsy; Behavior; Behavioral; Boston; Cells; Chronic; Clinical; Clinical Research; Cognition; Cognitive; Cognitive deficits; Communities; Data; Development; Disease; Doctor of Philosophy; Electroencephalography; Electrophysiology (science); Etiology; Functional disorder; Funding; Generations; Glutamates; Goals; Hallucinations; Head; Health; Health Care Costs; Healthcare Systems; Impaired cognition; In Vitro; Individual; Interneurons; K-Series Research Career Programs; Ketamine; Knock-out; Knockout Mice; Label; Link; Maintenance; Mediating; Methods; Modeling; Molecular; Motivation; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Neurons; Outcome; Patients; Pharmaceutical Preparations; Physiologic pulse; Physiological; Play; Population; Positioning Attribute; Postdoctoral Fellow; Prefrontal Cortex; Property; Psyche structure; Psychotic Disorders; Pyramidal Cells; Research; Resources; Rodent; Role; Schizophrenia; Scientist; Short-Term Memory; Slice; Symptoms; Synapses; System; Testing; Therapeutic; Training; Veterans; Viral; Viral Proteins; Work; analog; cognitive function; cognitive process; disability; executive function; experience; extracellular; frontal lobe; improved; in vitro Model; in vivo; insight; interest; medical schools; metabotropic glutamate receptor 5; neocortical; neural circuit; neurotransmission; next generation; novel; novel strategies; novel therapeutics; optogenetics; postnatal; pre-clinical; preclinical study; protein expression; receptor; research study; risk variant; skills; stem; therapeutic target

DESCRIPTION (provided by applicant): Candidate Background: I (Dr. James McNally, Ph.D.) currently serve as a postdoctoral fellow with the preclinical schizophrenia (Sz) research group headed by Dr. Robert W. McCarley, at the VA Boston Healthcare System (VABHS), Brockton campus. I have held this position since 2008 (~4.5 years), following completion of my Ph.D. studies at the UMass Medical School. Since joining this group, my research has been focused on elucidating the molecular mechanisms behind the cognitive deficits associated with schizophrenia (Sz). Sz is a devastating psychiatric illness, which affects ~1% of individuals over the age of 18. This disease warrants increased interest in the VA research community, given the higher instance of Sz among the veteran population, treatment of which accounts for some 40% of VA mental healthcare costs nationally. Veterans with Sz experience high levels of disability and poor community outcome. While clinically identified by the appearance of positive symptoms (psychosis, hallucinations) and negative symptoms (flattened affect, deficits in attention/motivation), deficits in fundamental cognitive processes (working memory, executive function) serve as a major determinant of the long-term disability associated with this illness. Current therapeutic strategies (first and second generation antipsychotics) do not satisfactorily address Sz-related cognitive issues. Thus, development of novel Sz therapeutics which better alleviate all symptom classes associated with this disease represents important clinical need. While the mechanisms responsible for the cognitive deficiencies associated with Sz remain poorly understood, they have been linked to abnormalities in gamma band (30-80 Hz) oscillations (GBO). Clinical and postmortem studies suggest that these abnormalities stem from impaired cortical circuitry. Recently I have developed a novel in vitro model to allow analysis of GBO at the single-neuron level. This model employs acute slices of mouse prelimbic cortex, the rodent analogue of the dorsolateral prefrontal cortex, an area heavily implicated in Sz related cognitive deficits. Presently we are using this system to model Sz-related abnormalities in GBO, and are exploring developmental alterations in this activity (see: Preliminary data and Appendix). Further, I have centrally involved in the development of in vivo methods using either optogenetic or auditory stimulation to evoke GBO in freely moving mice. I believe the combination of our in vitro and in vivo GBO models provide a powerful means to allow detailed analysis of the underlying mechanisms behind the generation of GBO, and potentially provide a means to evaluate new pharmacological therapeutic strategies specifically addressing the cognitive impairments associated with Sz. Current Proposal: Recent studies suggest that positive modulators of the type 5 metabotropic glutamate receptor (mGluR5) represent a novel class of antipsychotics with cognitive enhancing properties. In this revised proposal we will directly examine the effects of mGluR5 on the development and maintenance of the neocortical circuitry responsible for the generation of GBO. The overall hypothesis to be tested posits that mGluR5 mediated enhancement of NMDAR activity is essential for the proper development and maintenance of the neural circuitry responsible for GBO. Further, positive modulation of mGluR5 can alleviate Sz-like NMDAR hypofunction, and restore abnormal GBO observed in in vitro and in vivo NMDAR antagonist models of Sz. As the effects of mGluR5 on GBO have yet to be explored, this work is novel, and will provide valuable insight for the development of agents improving cognitive function in Sz. Long-Term Goals: If funded this VA Career Development Award will provide me with training in a number of areas critical to successful completion of the research proposed above (ie. targeted viral protein expression, optogenetics, in vivo electrophysiology). This increased skill set and experience will provide me the resources needed for my progression as a successful independent scientist in the VA research community.

描述（由申请人提供）： 候选人背景：I（I（James McNally博士，博士）目前是由Robert W. McCarley博士领导的临床前精神分裂症（SZ）研究小组的博士后研究小组，波士顿医疗保健系统（VABHS），布罗克顿校园。自2008年（〜4。5年）以来，我一直担任该职位。在UMass医学院学习。自加入该小组以来，我的研究一直集中在阐明与精神分裂症（SZ）相关的认知缺陷背后的分子机制。 SZ是一种毁灭性的精神病，影响了18岁以上约1％的人。鉴于在退伍军人人口中，SZ的较高实例值得增加对VA研究社区的兴趣，占全国VA心理保健成本的40％的治疗。 SZ的退伍军人经历了高水平的残疾和社区结果差。虽然通过临床症状（精神病，幻觉）和负面症状（扁平的情感，注意力/动机的缺陷）出现临床识别，但基本认知过程（工作记忆，执行功能）的缺陷是与这种疾病相关的长期残疾的主要决定因素。当前的治疗策略（第一代和第二代抗精神病药）并不能令人满意地解决与SZ相关的认知问题。因此，更好地减轻与这种疾病相关的所有症状类别的新型SZ疗法的发展代表了重要的临床需求。 虽然与SZ相关的认知缺陷的机制仍然鲜为人知，但它们与伽马频带（30-80 Hz）振荡（GBO）的异常有关。临床和验尸研究表明，这些异常源于皮质回路受损。最近，我开发了一种新型的体外模型，可以在单神经元水平上分析GBO。该模型采用了小鼠前皮层的急性切片，这是背外侧前额叶皮层的啮齿动物类似物，该区域与SZ相关的认知缺陷含量很大。目前，我们正在使用该系统对GBO中与SZ相关的异常进行建模，并正在探索此活动中的发展变化（请参阅：初步数据和附录）。此外，我使用光遗传学或听觉刺激在自由移动的小鼠中引起GBO的体内方法的开发。我相信我们的体外和体内GBO模型的结合提供了一种有力的手段，可以详细分析GBO产生背后的潜在机制，并有可能提供一种评估新的药理治疗策略的方法，专门解决与SZ相关的认知障碍。当前的建议：最近的研究表明，5型代谢型谷氨酸受体（MGLUR5）的阳性调节剂代表具有认知增强特性的新型抗精神病药。在此修订的建议中，我们将直接研究MGLUR5对负责GBO产生的新皮层电路的开发和维护的影响。要测试的总体假设假设MGLUR5介导的NMDAR活性增强对于正确发展和维持负责GBO的神经回路至关重要。此外，MGLUR5的阳性调节可以减轻SZ样NMDAR功能障碍，并恢复SZ的体外和体内NMDAR拮抗剂模型中观察到的异常GBO。由于MGLUR5对GBO的影响尚未探索，因此这项工作是新颖的，它将为改善SZ认知功能的代理的发展提供宝贵的见解。长期目标：如果资助该VA职业发展奖，将为我提供在成功完成上述研究至关重要的许多领域（即目标病毒蛋白表达，光遗传学，体内电生理学）。这种提高的技能和经验将为我提供我作为VA研究社区成功独立科学家的发展所需的资源。