lithium-chloride and Brain-Injuries--Traumatic

Experimental models of traumatic brain injury (TBI) recapitulate secondary injury sequela and cognitive dysfunction reported in patients afflicted with a TBI. Impairments in neurotransmission are reported in multiple brain regions in the weeks following experimental TBI and may contribute to behavioral dysfunction. Formation of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is an important mechanism for neurotransmitter exocytosis. We previously showed that lithium treatment attenuated hippocampal decreases in α-synuclein and VAMP2, enhanced SNARE complex formation, and improved cognitive performance after TBI. However, the effect of TBI on striatal SNARE complex formation is not known. We hypothesized lithium treatment would attenuate TBI-induced impairments in evoked dopamine release and increase the abundance of synaptic proteins associated with dopamine neurotransmission. The current study evaluated the effect of lithium (1 mmol/kg/day) administration on striatal evoked dopamine neurotransmission, SNARE complex formation, and proposed actions of lithium, including inhibition of GSK3β, assessment of synaptic marker protein abundance, and synaptic proteins important for dopamine synthesis and transport following controlled cortical impact (CCI). Sprague-Dawley rats were subjected to CCI or sham injury and treated daily with lithium chloride or vehicle for 7 days post-injury. We provide novel evidence that CCI reduces SNARE protein and SNARE complex abundance in the striatum at 1 week post-injury. Lithium administration improved evoked dopamine release and increased the abundance of α-synuclein, D2 receptor, and phosphorylated tyrosine hydroxylase in striatal synaptosomes post-injury. These findings show that lithium treatment attenuated dopamine neurotransmission deficits and increased the abundance of synaptic proteins important for dopamine signaling after TBI.

Topics: Animals; Brain Injuries, Traumatic; Corpus Striatum; Dopamine; Lithium Chloride; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; SNARE Proteins; Synaptic Transmission

Topics: Antimanic Agents; Brain Injuries, Traumatic; Humans; Lithium Chloride; Valproic Acid

Rodent models of traumatic brain injury (TBI) reproduce secondary injury sequela and cognitive impairments observed in patients afflicted by a TBI. Impaired neurotransmission has been reported in the weeks following experimental TBI, and may be a contributor to behavioral dysfunction. The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, the machinery facilitating vesicular docking and fusion, is a highly-conserved mechanism important for neurotransmission. Following TBI, there is a reduction in both the formation of the SNARE complex and the abundance of multiple SNARE proteins, including the chaperone protein cysteine string protein α (CSPα). Treatment with lithium in naïve rats reportedly increases the expression of CSPα. In the context of TBI, brain-injured rats treated with lithium exhibit improved outcome in published reports, but the mechanisms underlying the improvement are poorly understood. The current study evaluated the effect of lithium administration on the abundance of SNARE proteins and SNARE complex formation, hemispheric tissue loss, and neurobehavioral performance following controlled cortical impact (CCI). Sprague Dawley rats were subjected to CCI or sham injury, and treated daily with lithium chloride or vehicle for up to 14days. Administration of lithium after TBI modestly improved spatial memory at 14days post-injury. Semi-quantitative immunoblot analysis of hippocampal lysates revealed that treatment with lithium attenuated reductions in key SNARE proteins and SNARE complex formation at multiple time points post-injury. These findings highlight that treatment with lithium increased the abundance of synaptic proteins that facilitate neurotransmission and may contribute to improved cognitive function after TBI.

Topics: alpha-Synuclein; Analysis of Variance; Animals; Antimanic Agents; Brain Injuries, Traumatic; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Learning Disabilities; Lithium Chloride; Male; Psychomotor Disorders; Rats; Rats, Sprague-Dawley; SNARE Proteins; Spatial Learning; Synaptophysin; Synaptosomal-Associated Protein 25; Time Factors; Vesicle-Associated Membrane Protein 2