Impaired cognition is named as a major contributor to reduced quality of life in individuals living with a traumatic brain injury (TBI). Neuronal communication and normal brain function require regulated neurotransmitter release into the synaptic cleft. TBI results in impaired neurotransmitter release in multiple brain regions and can contribute to motor and cognitive dysfunction following injury; however, little is known about the mechanisms contributing to this impairment. Formation of the highly-conserved N-ethylmaleimide- sensitive factor attachment protein receptor (SNARE) complex facilitates vesicular docking and release of neurotransmitters, and reductions in SNARE complex formation are associated with impaired neurotransmission. In experimental rodent models of TBI, SNARE complex formation is reduced and the distribution of synaptic vesicles are altered in the weeks following injury. The synaptic vesicle glycoprotein 2A (SV2A) is an important regulator of the synaptic pool of readily releasable vesicles and SNARE complex formation. We have preliminary data that SV2A is reduced in synapses after TBI. SV2A was identified as the binding site of the FDA approved antiepileptic drug Levetiracetam (Keppra) in the brain. Furthermore, the Guidelines for Severe TBI cannot recommend Keppra without additional comparative studies. Keppra has been shown in a small number of reports to promote improved neurobehavioral function in rodent models of TBI, but the mechanism underlying this improvement is poorly understood. We have data showing treatment with Keppra can improve SNARE complex formation after TBI. The overall hypothesis is that SV2A plays a role in TBI-induced impaired neurotransmitter release, which can be restored with treatment of Keppra to improve neurotransmission.
Specific Aim 1 will determine the effect of TBI on SV2A abundance and SNARE complex formation in glutamatergic and GABAergic pre-synaptic terminals.
Specific Aim 2 will determine the effect of Keppra treatment on SV2A abundance, SNARE complex formation, and high-potassium evoked neurotransmitter release in the hippocampus after TBI. The contribution of SV2A in mediating the therapeutic effects of Keppra will be tested in SV2A knockout mice. Successful completion of this project will provide valuable insights into the understanding of synaptic dysfunction after TBI and potential benefits for clinical usage of Keppra in TBI patients.
Traumatic brain injury results in disrupted neuronal communication as a result of impaired neurotransmitter release. In this study, we will evaluate the contribution of the synaptic protein SV2A in impaired neurotransmitter release, and the effect of the antiepileptic drug Levetiracetam on SV2A and neurotransmitter release after TBI. Successful completion of this project may provide insight into synaptic dysfunction after TBI and potential benefits for clinical usage of Keppra in TBI patients.
