Neurogranin and Traumatic Brain Injury

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Deployed and nondeployed military personnel are at higher risk of traumatic brain injury (TBI) than civilians. TBI of all severities can result in chronic disturbances of cognitive, behavioral, emotional, and physical functioning. Learning, memory and attention are especially vulnerable across the spectrum of TBI injury severity and symptoms may persist years to decades. While most TBIs experienced by Veteran’s are mild, enduring a severe TBI produces significant personal, societal and economic burden. TBIs that require hospitalization account for approximately 90% of total TBI medical costs. There are currently no FDA-approved pharmacotherapies to treat TBI. Thus, research to develop new pharmacotherapies for TBI will benefit Veterans with persistent posttraumatic neurocognitive disabilities. These impairments have been recapitulated in pre- clinical TBI models. Animals demonstrate poor performance on cognitive tasks along with associated pathological synaptic communication on molecular, anatomical and electrophysiological scales. Furthermore, these models for the investigation of underlying cellular mechanisms and potential therapeutic targets of TBI associated impairments. Synaptic strength and plasticity are believed to underlie learning and memory behaviors. Dysfunction of synapses is one of the earliest and most common abnormalities preceding neuronal death in neurodegenerative diseases and has been reported in several animal models of TBI. Neurogranin (Ng), a post-synaptic protein localized to post-synaptic dendritic spines, notably regulates synaptic plasticity through calcium-dependent temporal and spatial regulation of calmodulin (CaM). Synaptic activity leads to precisely timed changes in Ng phosphorylation by protein kinase C (PKC). This is synchronized with Ca2+-CaM downstream signaling and Calcium-Calmodulin Kinase II (CaMKII) activation via autophosphorylation. Ng modulates synaptic excitability through these pathways. CSF and blood levels of Ng have also been used as biofluid biomarkers of synaptic neurodegeneration in Alzheimer’s disease and other neurodegenerative syndromes, as well as in acute TBI. Recently, chronic decreases in plasma exosome levels of Ng was seen in combat-deployment-related mild TBI. Our recent findings showed significantly reduced Ng protein expression in the rat cortex and hippocampus up to two weeks after controlled cortical impact, particularly in the CA1 and CA3 of the hippocampus. This evidence suggests Ng’s potential involvement in pathological mechanisms of learning and memory difficulties after TBI. The overall hypothesis is that decreased Ng expression contributes to dysfunctional synaptic plasticity and cognition after TBI. Specific Aim 1 will examine the effects of TBI on Ng signaling, associated synaptic proteins and dendritic morphology. Preliminary data shows Ng is detectable in serum in sham and CCI-injured animals at two weeks post-injury. Thus, for the first time, an experimental model can be utilized to directly study the relationship between biofluid Ng levels and conformational synaptic neuropathology. Specific Aim 2 will next examine using adeno-associated viral (AAV) delivery to increase neuronal Ng in the hippocampus. Retinoic acid (RA), a metabolite of Vitamin A, increases Ng protein levels and has been identified as a potential pharmacotherapeutic for ischemic injury and other neurological disorders. Specific Aim 3 will determine the effects of RA therapy on Ng signaling, synaptic neurodegeneration, and cognitive function after TBI. Successful completion of this study will identify Ng as a therapeutic target and biomarker of synaptic dysfunction in TBI.