Glutamate, the predominant excitatory neurotransmitter in the central nervous system, is released from multiple stores after a TBI, as primary mechanical forces from the injury can breakdown the blood-brain-barrier and create pores in cell membranes leading to glutamate release into the extracellular space. In addition, redistribution of ions after the injury can create a massive depolarization leading to neuronal release of glutamate [1-3]. Glutamate plays a pivotal role in the pathophysiology of secondary damage after injury by excessively activating ionotropic glutamate receptors, disrupting ionic homeostasis, increasing the energy demand of the cell, and producing reactive oxygen species [4-7]. Increased glutamate levels could produce excessive excitation and neuronal damage that may be responsible for motor, behavioral, and cognitive deficits following TBI. Central hypothesis: TBI alters glutamate regulation elevating the extracellular concentration of glutamate.
Specific Aims : (1) TBI increases tonic glutamate levels and neuronal release of glutamate, (2) TBI decreases the ability of glutamate transporters to clear glutamate from the extracellular space, (3) Elevated extracellular levels of glutamate contribute to the post-traumatic pathophysiology, (4) Pretreatment with a recently developed adeno-associated virus expressing the glutamate transporter GLT-1 (AAV1-GLT-1) will improve glutamate regulation and motor function after injury. The proposed project examines TBI induced alterations in glutamate signaling using a novel technology, enzyme-based microelectrode arrays (MEAs) coupled with in vivo amperometry. MEAs allow for selective measures of extracellular glutamate and measure the fast dynamics of glutamate release and uptake involved in glutamate neurotransmission. Examining injury-induced alterations in glutamate signaling in different regions of the central nervous system may reveal specific mechanisms responsible for increased extracellular glutamate levels. Monitoring extracellular levels of glutamate in awake animals for multiple days after injury will examine if increases in extracellular glutamate contribute to post-traumatic pathophysiology. These studies may reveal important mechanistic discoveries and the therapeutic window available to improve motor, behavioral, and cognitive outcomes following TBI. Finally, we will examine if pretreatment with AAV1- GLT-1 can improve glutamate regulation and reduce motor deficits after injury.
Approximately 1.5 million Americans suffer from a traumatic brain injury (TBI) each year, with mild TBI accounting for as many as 75% of all the injuries . Survivors of TBI suffer from a wide spectrum of deficits, including impairments in working memory, attention, learning, cognitive function, and motor function [9-13]. Future research needs to examine the pathological mechanisms responsible for producing these deficits, which may provide novel therapeutic targets to improve outcomes after injury.
|Hinzman, Jason M; Thomas, Theresa Currier; Quintero, Jorge E et al. (2012) Disruptions in the regulation of extracellular glutamate by neurons and glia in the rat striatum two days after diffuse brain injury. J Neurotrauma 29:1197-208|
|van Bregt, Daniel R; Thomas, Theresa Currier; Hinzman, Jason M et al. (2012) Substantia nigra vulnerability after a single moderate diffuse brain injury in the rat. Exp Neurol 234:8-19|
|Harvey, Brandon K; Airavaara, Mikko; Hinzman, Jason et al. (2011) Targeted over-expression of glutamate transporter 1 (GLT-1) reduces ischemic brain injury in a rat model of stroke. PLoS One 6:e22135|