Improving cortical function & cognition in schizophrenia by modulation of mGluR5

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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.