Improving cortical function & cognition in schizophrenia by modulation of mGluR5

描述（由申请人提供）： 候选人背景：我（博士詹姆斯麦克纳利，博士）目前担任博士后研究员与临床前精神分裂症（Sz）研究小组为首的博士罗伯特W。麦卡利，在弗吉尼亚州波士顿医疗保健系统（VABHS），布罗克顿校园。我从2008年（约4.5年）开始担任这个职位，在我完成博士学位后。在麻省大学医学院学习。自从加入这个小组以来，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疾病，影响18岁以上人群的约1%。鉴于退伍军人中Sz的实例较高，这种疾病值得在VA研究界增加兴趣，其治疗占全国VA精神卫生保健费用的40%左右。患有Sz的退伍军人经历了高水平的残疾和糟糕的社区结果。虽然临床上通过出现阳性症状（精神病、幻觉）和阴性症状（情感淡漠、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）的缺陷是与这种疾病相关的长期残疾的主要决定因素。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SZ相关的认知问题。因此，更好地缓解与该疾病相关的所有症状类别的新型Sz治疗剂的开发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知之甚少，但它们与伽马波段（30-80 Hz）振荡（GBO）异常有关。临床和尸检研究表明，这些异常源于受损的皮质回路。最近，我开发了一种新的体外模型，允许在单神经元水平上分析GBO。该模型采用小鼠前边缘皮层的急性切片，背外侧前额叶皮层的啮齿类动物类似物，该区域严重涉及Sz相关的认知缺陷。目前，我们正在使用这个系统来模拟GBO中与SZ相关的异常，并正在探索这种活动的发育变化（见：初步数据和附录）。此外，我主要参与了体内方法的开发，这些方法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模型的组合提供了一种强大的手段，可以详细分析GBO产生背后的潜在机制，并可能提供一种方法来评估新的药理学治疗策略，特别是解决与Sz相关的认知障碍。当前提案：最近的研究表明，5型代谢型谷氨酸受体（mGluR 5）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，我们将直接研究mGluR 5对负责GBO生成的新皮层回路的发展和维持的影响。待检验的总体假设假定mGluR 5介导的NMDAR活性增强对于负责GBO的神经回路的适当发育和维持是必不可少的。此外，mGluR 5的正调节可以减轻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mGluR 5对GBO的影响尚未被探索，这项工作是新颖的，并将为开发改善Sz认知功能的药物提供有价值的见解。长期目标：如果资助这个VA职业发展奖将为我提供培训，在一些关键领域的成功完成上述研究建议（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提供所需的资源，我的进步作为一个成功的独立科学家在VA研究社区。

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.