Department of Neurological Surgery, Safar Center for Resuscitation Research, VA Pittsburgh Healthcare System, University of Pittsburgh , Pittsburgh, Pennsylvania.
J Neurotrauma. 2018 Dec 1;35(23):2827-2836. doi: 10.1089/neu.2017.5509. Epub 2018 Aug 13.
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.
创伤性脑损伤（TBI）的实验模型再现了外伤性脑损伤患者报告的继发性损伤后遗症和认知功能障碍。在实验性 TBI 后的数周内，多个脑区报道了神经递质传递受损，这可能导致行为功能障碍。可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）复合物的形成是神经递质胞吐的重要机制。我们之前的研究表明，锂治疗可减轻海马区α-突触核蛋白和 VAMP2 的减少，增强 SNARE 复合物的形成，并改善 TBI 后的认知表现。然而，TBI 对纹状体 SNARE 复合物形成的影响尚不清楚。我们假设锂治疗可减轻 TBI 引起的诱发多巴胺释放受损，并增加与多巴胺神经传递相关的突触蛋白的丰度。本研究评估了锂（1mmol/kg/天）给药对纹状体诱发多巴胺神经传递、SNARE 复合物形成的影响，以及锂的作用，包括抑制 GSK3β、评估突触标记蛋白丰度以及对多巴胺合成和转运很重要的突触蛋白，在皮质撞击（CCI）后。斯普拉格-道利大鼠接受 CCI 或假损伤，并在损伤后每天用氯化锂或载体处理 7 天。我们提供了新的证据表明，CCI 在损伤后 1 周降低了纹状体中的 SNARE 蛋白和 SNARE 复合物的丰度。锂给药改善了损伤后纹状体中的诱发多巴胺释放，并增加了突触体中的α-突触核蛋白、D2 受体和磷酸化酪氨酸羟化酶的丰度。这些发现表明，锂治疗可减轻 TBI 后多巴胺神经传递缺陷并增加对多巴胺信号很重要的突触蛋白的丰度。
