G-protein Signaling Reduces Neurodegeneration and Promotes Recovery of Synaptic Strength following Traumatic Brain Injury

The current proposal is directly relevant to several of the scientific priority areas outlined by the Board. We propose to examine, for the first time, the role of the Rit GTPase in the response of the adult brain to traumatic brain injury (TBI). We have found that the Rit GTPase (RIT1) is dramatically down-regulated following a unilateral cortical contusion injury (CCI), prompting studies to explore the contribution of Rit-directed signaling to functional recovery following TBI. Ongoing studies suggest that Rit activity significantly reduces in vivo neurodegeneration in the hippocampus and cortex, promotes synaptic integrity, and reduces cognitive and motor dysfunction following contusion injury. Through these studies we will provide new insights into the biological characterization of the well-established controlled cortical impact (CCI) brain injury model of contusion, with a focus on the vulnerability of hippocampal neurons, a neuronal population whose death has important implications for posttraumatic cognitive impairment (Priority Area 3). We use a coordinated approach coupling in vivo and in vitro studies to study the role of active Rit in neuronal survival and recovery of synaptic function following contusion injury. Specifically, we propose to examine how Rit signaling promotes neuroprotection and reduces cognitive dysfunction, with a focus on the ability of Rit to protection against dendritic and synaptic degeneration. An increased understanding of neuronal survival and recovery of synaptic strength in the setting of TBI should lead to strategies to improve the brain’s inherent ability to restore compromised circuitry following injury (Priority Area 1). Finally, through an increased understanding of the role that Rit plays in the preservation of neurons/synaptic function after TBI, our proposed studies are expected to stimulate new strategies designed to increase brain recovery and lessen functional deficits after trauma (Priority Area 5).