The role of metabotropic mGluR2 receptors in the chronic cognitive and behavioral effects of blast exposure

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Traumatic brain injury (TBI) has been linked to a variety of chronic mental health problems in veterans. A striking feature in the most recent veterans returning from Iraq and Afghanistan has been the overlap between a history of blast-related mild TBI (mTBI) and post-traumatic stress disorder (PTSD). In many symptoms that follow mTBI persist and evolve into a chronic postconcussion syndrome. In addition, in some new symptoms develop or old symptoms progress and mounting evidence suggests TBI is a risk factor for later development of neurodegenerative diseases. In collaboration with a Department of Defense investigator, Dr. Stephen Ahlers, we have been studying a rat model of blast overpressure injury that was developed to mimic a blast- related human mild TBI or subclinical blast exposure. Prior work established that blast-exposed animals exhibit chronic cognitive and PTSD-related behavioral traits that are present for over one year after blast exposure. Recent work has shown that these traits develop in a delayed and progressive manner. Since prior studies found that a group II metabotropic receptor (mGluR2/3) antagonist reversed many blast-induced behavioral traits, we explored mGluR2/3 expression after blast and found mGluR2 increased after blast exposure at 43 weeks or more in brain and at six weeks in isolated vascular fractions. Our collaborator Dr. David Cook (Puget Sound VA) has found increased immunohistochemical staining for mGluR2/3 in post-mortem brain tissue from blast-exposed veterans with chronic neurobehavioral syndromes. These studies support alterations in mGluR2 receptors as a key pathophysiological event following blast injury. In Specific Aim #1 using blast-exposed rats we will examine the time dependence of mGluR2 expression within the neuronal and neurovascular compartments and how expression correlates with appearance of the delayed behavioral phenotype. Specific Aim #2 will examine the downstream molecular effects of increased mGluR2 expression as well as determine the mGluR2 dependence of the behavioral phenotype by blast exposing mGluR2 KO rats or knocking down mGluR2 on a regional basis using adeno associated viral (AAV) vectors. Specific Aim #3 will determine whether (2R,6R)-hydroxynorketamine can reverse blast-related cognitive and behavioral traits in rats. In Specific Aim #4 in collaboration with Dr. Cook we will determine whether mGluR2 expression is altered in post mortem brain from veterans with chronic neurobehavioral syndromes following blast exposure using tissue from veterans and military service members collected at the Puget Sound VA or provided by Dr. Dan Perl (Uniformed Services University of the Health Sciences). These studies will test the hypothesis that altered mGluR2 expression is a feature of blast-related brain injury in veterans as well as experimental animal models and further test the role of mGluR2 as a therapeutic target in the neurobehavioral syndromes that follow blast injury.