Project Summary The occurrence of concussion, or mild TBI, has been steadily increasing in incidence over the past decade. One possible consequence of concussion - post-concussion syndrome - can persist for weeks to months and result in life dissatisfaction for the patient and economic burden for society. With the development of new rodent models for mild TBI, we can now study the molecular mechanisms that mediate injury and/or protection from a single TBI. Our previous work identified significant changes in the guanine deaminase cytosolic PSD-95 interactor (cypin) after mild and moderate TBI, and in turn, discovered small molecule cypin activators that are neuroprotective in vitro and restore neurocognition in vivo in both mild and moderate TBI models. Cellular concentrations of methionine, a key metabolic effector that regulates neurocognition, increases shortly after mild TBI, and our preliminary data point to cypin as a pivotal molecule for restoring methionine levels to baseline after TBI. We are proposing that activation of purine metabolism by cypin attenuates methionine levels via two mechanisms: 1) by altering cellular metabolism needed for methionine production and 2) by binding to adenosylhomocysteinase like 1 (AHCYL1), sequestering it from inhibiting adenosylhomocysteinase, allowing the methionine cycle to continue and reducing methionine accumulation post-mTBI. These mechanisms can be harnessed for therapeutic application. Our proposed work determines whether the activation of cypin can be targeted after mild TBI to promote functional recovery in mice. Broadly, our proposed experiments will identify new molecular targets for treating TBI patients and reducing the long-term morbidity of TBI on society.

Project Narrative Concussion, or mild traumatic brain injury (mTBI), is the most common neurological condition seen in both children and adults, and the incidence of concussions is increasing with a growing awareness of the possible consequences of repetitive concussions on brain health. We identified a protein that protects cognition and accelerates recovery after moderate TBI. The current studies will address whether therapeutics that target this protein can be used to promote recovery after a single mild TBI, paving the way for future drug development for human use.