Kelso Matthew L, Wehner Jeanne M, Collins Allan C, Scheff Stephen W, Pauly James R
College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Brain Res. 2006 Apr 14;1083(1):204-10. doi: 10.1016/j.brainres.2006.01.127. Epub 2006 Mar 20.
The alpha7 nicotinic cholinergic receptor is a ligand-gated ion channel with calcium permeability similar to that of ionotrophic glutamate receptors. Previous studies from our laboratory have implicated changes in expression alpha7 nicotinic cholinergic receptors in the pathophysiology of traumatic brain injury (TBI). In rats, TBI causes a time-dependent and significant decrease in cortical and hippocampal alpha-[(125)I]-bungarotoxin (BTX) binding. We have postulated that deficits in alpha7 expression may contribute to TBI-induced cognitive impairment and that nicotinic receptor agonists can reverse alpha7 binding deficits and result in significant cognitive improvement compared to saline-treated controls. Thus, alpha7 nAChRs could be involved in a form of cholinergically mediated excitotoxicity following brain injury. In the current study, wild-type, heterozygous and null mutant mice were employed to test the hypothesis that genotypic depletion of the alpha7 receptor would render animals less sensitive to tissue loss and brain inflammation following experimental brain injury. Mice were anesthetized and subjected to a 0.5-mm cortical contusion injury of the somatosensory cortex. Brain inflammation, changes in nicotinic receptor expression and cortical tissue sparing were evaluated in wild-type, heterozygous and homozygous mice 1 week following TBI. In wild-type mice, brain injury caused a significant decrease in BTX binding in several hippocampal regions, consistent with what we have measured in rat brain following TBI. However, there were no genotypic differences in cortical tissue sparing or brain inflammation in this experiment. Although the results of this study were largely negative, it is still plausible that changes in the activity/expression of native alpha7 receptors contribute to pathophysiology following TBI. However, when null mutant mice develop in the absence of central alpha7 expression, it is possible that compensatory changes occur that confound the results obtained.
α7烟碱型胆碱能受体是一种配体门控离子通道，其钙通透性与离子型谷氨酸受体相似。我们实验室之前的研究表明，α7烟碱型胆碱能受体的表达变化与创伤性脑损伤（TBI）的病理生理学有关。在大鼠中，TBI导致皮质和海马中α-[(125)I]-银环蛇毒素（BTX）结合呈时间依赖性显著下降。我们推测，α7表达缺陷可能导致TBI诱导的认知障碍，与生理盐水处理的对照组相比，烟碱受体激动剂可以逆转α7结合缺陷并显著改善认知。因此，α7烟碱型乙酰胆碱受体可能参与脑损伤后胆碱能介导的兴奋性毒性形式。在本研究中，使用野生型、杂合子和纯合突变小鼠来检验以下假设：α7受体的基因缺失会使动物在实验性脑损伤后对组织损失和脑炎症的敏感性降低。小鼠麻醉后，对体感皮层进行0.5毫米的皮质挫伤损伤。在TBI后1周，对野生型、杂合子和纯合小鼠的脑炎症、烟碱受体表达变化和皮质组织保留情况进行评估。在野生型小鼠中，脑损伤导致几个海马区域的BTX结合显著下降，这与我们在大鼠脑TBI后测量的结果一致。然而，在本实验中，皮质组织保留或脑炎症方面没有基因型差异。尽管本研究结果大多为阴性，但天然α7受体的活性/表达变化仍可能导致TBI后的病理生理学变化。然而，当纯合突变小鼠在没有中枢α7表达的情况下发育时，可能会发生补偿性变化，从而混淆所获得的结果。
