Lithium as a Therapeutic Approach to Attenuate Synaptic Deficits after TBI

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 DESCRIPTION (provided by applicant): A TBI produces complex pathophysiology contributing to progressive cellular dysfunction and death that can culminate in impaired motor and cognitive abilities. Despite advances in understanding the multifaceted pathobiology of traumatic brain injury (TBI), no therapeutic has been approved for the treatment of TBI in clinical trials. Previous work from our lab demonstrates that deficits in acetylcholine release in the hippocampus contribute to the manifestation of neurobehavioral dysfunction after injury, but little is known about the mechanisms underlying impaired neurotransmission. In the uninjured brain, the formation of the N- ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex facilitates vesicular docking and neurotransmitter release; however, the effects of TBI on the SNARE complex have not been examined. We hypothesize that alterations in the SNARE complex and synaptic vesicle distribution contribute to impaired neurotransmission and behavioral dysfunction after TBI. The proposed work will test the efficacy of lithium to attenuate intrasynaptic impairments, promote synaptic plasticity and cell survival, and improve neurobehavioral function after TBI. To this end, we will utilize rat and mouse models of TBI to examine the therapeutic capacity of lithium. Additionally, we will examine the specificity of lithium's action in the synapse using commercially available cysteine string protein alpha (CSPa) knockout mice. In Aim 1, we will evaluate the effect of lithium on SNARE protein abundance and complex formation at multiple time points after TBI. Additionally, we will examine the effect of lithium on synaptic vesicular distribution and density and neurotransmitter release after TBI by transmission electron microscopy and microdialysis, respectively. In Aim 2, we will examine the effect of lithium on synaptic plasticity, hippocampal neuron survival, and neurobehavioral function in the weeks following TBI. The proposed work will provide the first evaluation of changes in synaptic vesicle distribution and alterations in the SNARE complex after TBI. Successful completion of this work will provide valuable insights into our understanding of synaptic dysfunction and the development of lithium based approaches to promote recovery in the injured brain.