Improving cortical function & cognition in schizophrenia by modulation of mGluR5

描述(由申请人提供)： 候选人背景：我(詹姆斯·麦克纳利博士，博士)目前在弗吉尼亚州波士顿医疗系统(VABHS)布罗克顿校区担任由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员。自2008年(约4.5年)以来，我一直担任这一职位，当时我在加州大学马萨诸塞州医学院完成了博士学业。自从加入这个小组以来，我的研究一直专注于阐明与精神分裂症(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岁以上约1%的人。鉴于退伍军人中SZ的发病率较高，这种疾病理应引起退伍军人研究社区的更大兴趣，其治疗占全国退伍军人精神卫生保健费用的40%左右。患有SZ的退伍军人残疾程度很高，社区结果很差。虽然临床上通过出现积极症状(精神病、幻觉)和消极症状(情感平淡、注意力/动力不足)来确定，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物)不能令人满意地解决与Sz相关的认知问题。因此，开发新的Sz疗法以更好地缓解与这种疾病相关的所有症状类别具有重要的临床需求。虽然与Sz相关的认知缺陷的机制仍然知之甚少，但它们已被认为与伽玛波段(30-80赫兹)振荡(GBO)的异常有关。临床和尸检研究表明，这些异常源于皮质回路受损。最近，我开发了一种新的体外模型，可以在单个神经元水平上分析GBO。这个模型使用了小鼠前脑皮质的急性切片，这是啮齿类动物的前额叶背外侧皮质，该区域与Sz相关的认知缺陷密切相关。目前，我们正在使用这个系统来模拟GBO中与Sz相关的异常，并正在探索这一活动中的发育变化(见：初步数据和附录)。此外，我主要参与了体内方法的开发，使用光遗传或听觉刺激在自由活动的小鼠中唤起GBO。我相信，我们的体外和体内GBO模型的结合为详细分析GBO产生的潜在机制提供了强大的手段，并可能提供一种评估专门针对与Sz相关的认知障碍的新的药物治疗策略的手段。目前建议：最近的研究表明，5型代谢性谷氨酸受体(MGluR5)的正向调节剂代表了一类具有认知增强特性的新型抗精神病药物。在这项修订后的提案中，我们将直接研究mGluR5对负责产生GBO的新皮质回路的发育和维持的影响。有待检验的总体假设是，mGluR5介导的NMDAR活性的增强对于负责GBO的神经回路的正确发展和维持至关重要。此外，mGluR5的正向调节可以减轻Sz样NMDAR功能低下，并恢复在体内和体外NMDAR拮抗剂模型中观察到的异常GBO。由于mGluR5对GBO的影响尚不清楚，因此这项工作是新颖的，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：如果得到资助，这个退伍军人职业发展奖将在一些领域为我提供培训，这些领域对于成功完成上述建议的研究至关重要(即。靶向病毒蛋白表达、光遗传学、体内电生理学)。这套增加的技能和经验将为我在退伍军人管理局研究界成为一名成功的独立科学家提供所需的资源。

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.