Traumatic Brain Injury (TBI) can result in the disturbance of cognitive, behavioral, emotional, and physical functioning. Normal brain cognitive function depends on synaptic communication via neurotransmitter release. TBI can produce persistent deficits in both dopaminergic and cholinergic evoked neurotransmitter release, but the mechanisms are unknown. Neurotransmitter release at the synapse requires fusion of synaptic vesicles with the presynaptic plasma membrane. A crucial step in this process involves the assembly of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, a highly stable, parallel four-helix bundle formed between the synaptic vesicle SNARE synaptobrevin 2 (syb2) and the plasma membrane SNAREs syntaxin 1 and synaptosome-associated protein of 25 kDa (SNAP-25). The pathology of SNARE proteins may play an important role in TBI, especially concerning neurotransmission and subsequent cognitive disturbances. Cysteine string protein alpha (CSP?) promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity. It has recently been discovered that lithium, at therapeutically relevant concentrations, can enhance the expression of CSP?. This represents a novel mechanism by which lithium may restore neurotransmitter release deficits after TBI. To further evaluate the role of CSP? in mediating lithium's effect on SNARE proteins and cognitive recovery after TBI, this project will evaluate lithium therapy in a CSP? transgenic mouse. The goal of this proposal is to examine SNARE-complex mechanisms of neurotransmission deficits after TBI. The overall hypothesis is that cognitive deficits following TBI may be, at least partialy, attributable to impairment in synaptic SNARE-complex formation and subsequent neurotransmitter release deficits.
Specific Aim 1 will examine the effects of TBI on individual SNARE proteins, SNARE- complex assembly, and CSP?, a key regulator of SNARE-complex assembly.
Specific Aim 2 will determine if increasing the expression of CSP? by lithium is associated with a restoration of SNARE-complex assembly and evoked neurotransmitter release as measured by microdialysis.
Specific Aim 3 will determine if lithium can attenuate cognitive deficits after TBI. Successful completion of this project may provide evidence that SNARE-complexes are diminished after TBI and identify a novel application of lithium for the treatment of posttraumatic cognitive deficits.

Public Health Relevance

Approximately 1.7 million people sustain traumatic brain injury (TBI) each year in the United States and more than 5.3 million people live with disabilities caused by TBI. In this study, we will investigate a new mechanism of cognitive post-traumatic cognitive deficits and will evaluate lithium therapy as a countermeasure. If successful, this study would lead to the development of a new use for an FDA-approved drug for the treatment of memory deficits after TBI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS079061-02
Application #
8539648
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Hicks, Ramona R
Project Start
2012-09-15
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$319,807
Indirect Cost
$108,713
Name
University of Pittsburgh
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Bondi, Corina O; Semple, Bridgette D; Noble-Haeusslein, Linda J et al. (2015) Found in translation: Understanding the biology and behavior of experimental traumatic brain injury. Neurosci Biobehav Rev 58:123-46
Yan, Hong Q; Shin, Samuel S; Ma, Xiecheng et al. (2014) Differential effect of traumatic brain injury on the nuclear factor of activated T Cells C3 and C4 isoforms in the rat hippocampus. Brain Res 1548:63-72
Kochanek, Patrick M; Berger, Rachel P; Fink, Ericka L et al. (2013) The potential for bio-mediators and biomarkers in pediatric traumatic brain injury and neurocritical care. Front Neurol 4:40