Positive allosteric modulation of the α7 nicotinic acetylcholine receptor as a treatment for cognitive deficits after traumatic brain injury

Cognitive impairments are a common consequence of traumatic brain injury (TBI). The hippocampus is a subcortical structure that plays a key role in the formation of declarative memories and is highly vulnerable to TBI. The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in the hippocampus and reduced expression and function of this receptor are linked with cognitive impairments in Alzheimer’s disease and schizophrenia. Positive allosteric modulation of α7 nAChRs with AVL-3288 enhances receptor currents and improves cognitive functioning in naïve animals and healthy human subjects. Therefore, we hypothesized that targeting the α7 nAChR with the positive allosteric modulator AVL-3288 would enhance cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury or sham surgery. At 3 months after recovery, animals were treated with vehicle or AVL-3288 at 30 min prior to cue and contextual fear conditioning and the water maze task. Treatment of TBI animals with AVL-3288 rescued learning and memory deficits in water maze retention and working memory. AVL-3288 treatment also improved cue and contextual fear memory when tested at 24 hr and 1 month after training, when TBI animals were treated acutely just during fear conditioning at 3 months post-TBI. Hippocampal atrophy but not cortical atrophy was reduced with AVL-3288 treatment in the chronic recovery phase of TBI. AVL-3288 application to acute hippocampal slices from animals at 3 months after TBI rescued basal synaptic transmission deficits and long-term potentiation (LTP) in area CA1. Our results demonstrate that AVL-3288 improves hippocampal synaptic plasticity, and learning and memory performance after TBI in the chronic recovery period. Enhancing cholinergic transmission through positive allosteric modulation of the α7 nAChR may be a novel therapeutic to improve cognition after TBI.

认知障碍是创伤性脑损伤（traumatic brain injury, TBI）的常见并发症。海马体（hippocampus）作为皮层下结构（subcortical structure），在陈述性记忆（declarative memories）的形成过程中发挥关键作用，且对TBI损伤高度易感。α7烟碱型乙酰胆碱受体（α7 nicotinic acetylcholine receptor, nAChR）在海马体中呈高表达状态，该受体的表达与功能下调，与阿尔茨海默病（Alzheimer’s disease）、精神分裂症（schizophrenia）患者的认知障碍密切相关。采用AVL-3288对α7 nAChR进行正变构调节（positive allosteric modulation），可增强受体电流，并改善未处理动物（naïve animals）与健康人体的认知功能。据此，我们提出假说：通过正变构调节剂AVL-3288靶向α7 nAChR，可改善TBI慢性恢复期的认知功能。为验证该假说，成年雄性斯普拉格-道利大鼠（Sprague Dawley rats）接受中度矢状旁液压冲击脑损伤（moderate parasagittal fluid-percussion brain injury）或假手术（sham surgery）。术后恢复3个月时，分别在线索与情境恐惧条件反射（cue and contextual fear conditioning）训练及水迷宫任务（water maze task）训练前30分钟，对各组动物施以赋形剂（vehicle）或AVL-3288处理。对TBI模型大鼠给予AVL-3288干预，可挽救其在水迷宫留存测试与工作记忆任务中的学习记忆缺陷（learning and memory deficits）。在训练后24小时及1个月时进行检测，当TBI模型大鼠仅在伤后3个月的恐惧条件反射阶段接受急性AVL-3288处理时，其线索与情境恐惧记忆同样得到改善。在TBI慢性恢复期，AVL-3288处理可减轻海马萎缩（hippocampal atrophy），但对皮层萎缩（cortical atrophy）无显著改善作用。将AVL-3288应用于TBI造模后3个月大鼠的急性海马脑片，可挽救其CA1区的基础突触传递（basal synaptic transmission）缺陷与长时程增强（long-term potentiation, LTP）损伤。本研究结果证实，AVL-3288可改善TBI慢性恢复期大鼠的海马突触可塑性（synaptic plasticity）及学习记忆能力。通过对α7 nAChR进行正变构调节以增强胆碱能传递（cholinergic transmission），或可成为改善TBI后认知功能的新型治疗策略（therapeutic）。