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：我（James McNally 博士）目前在布罗克顿 VA 波士顿医疗系统 (VABHS) 的 Robert W. McCarley 博士领导的临床前精神分裂症 (Sz) 研究小组担任博士后研究员校园。我自 2008 年完成博士学位后（约 4.5 年）起担任该职位。在麻省大学医学院学习。自从加入这个小组以来，我的研究重点是阐明与精神分裂症（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疾病，约 1% 的 18 岁以上个体受到影响。鉴于退伍军人群体中 Sz 的发病率较高，且接受治疗的人员约占 40%，因此退伍军人管理局研究界对这种疾病的兴趣日益浓厚退伍军人管理局全国心理保健费用。患有 Sz 的退伍军人会经历严重的残疾和较差的社区成果。虽然临床上通过出现阳性症状（精神病、幻觉）和阴性症状（情绪低落、注意力/动机缺陷）来识别，但基本认知过程（工作记忆、执行功能）的缺陷是长期症状的主要决定因素。与这种疾病相关的残疾。目前的治疗策略（第一代和第二代抗精神病药）不能令人满意地解决与 Sz 相关的认知问题。因此，开发能够更好地缓解与该疾病相关的所有症状类别的新型 Sz 疗法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知之甚少，但它们与伽马带（30-80 Hz）振荡（GBO）异常有关。临床和尸检研究表明，这些异常源于皮质回路受损。最近，我开发了一种新型体外模型，可以在单神经元水平上分析 GBO。该模型采用小鼠前边缘皮质的急性切片，啮齿类动物的背外侧前额皮质类似物，该区域与 Sz 相关的认知缺陷密切相关。目前，我们正在使用该系统来模拟 GBO 中与 Sz 相关的异常，并正在探索该活动的发育改变（参见：初步数据和附录）。此外，我主要参与了体内方法的开发，使用光遗传学或听觉刺激在自由移动的小鼠中诱发 GBO。我相信我们的体外和体内 GBO 模型的结合提供了一种强大的手段，可以详细分析 GBO 生成背后的潜在机制，并有可能提供一种评估新药理学治疗策略的方法，特别是针对与 Sz 相关的认知障碍。目前的提议：最近的研究表明，5 型代谢型谷氨酸受体 (mGluR5) 的正调节剂代表了一类具有认知增强特性的新型抗精神病药。在这个修订后的提案中，我们将直接检查 mGluR5 对负责生成 GBO 的新皮质回路的发育和维持的影响。待测试的总体假设认为，mGluR5 介导的 NMDAR 活性增强对于负责 GBO 的神经回路的正确发育和维持至关重要。此外，mGluR5的正向调节可以缓解Sz样NMDAR功能减退，并恢复在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 的影响尚未被探索，这项工作是新颖的，将为开发改善 Sz 认知功能的药物提供有价值的见解。长期目标：如果获得资助，该 VA 职业发展奖将为我提供对成功完成上述研究至关重要的许多领域的培训（即靶向病毒蛋白表达、光遗传学、体内电生理学）。这种增加的技能和经验将为我在退伍军人事务部研究界成为一名成功的独立科学家提供所需的资源。