The Miami Project to Cure Paralysis, Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL 33136, USA.
Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minneapolis, MN, USA.
Exp Neurol. 2024 Feb;372:114647. doi: 10.1016/j.expneurol.2023.114647. Epub 2023 Dec 8.
Traumatic brain injury (TBI) results in several pathological changes within the hippocampus that result in adverse effects on learning and memory. Therapeutic strategies to enhance learning and memory after TBI are still in the early stages of clinical development. One strategy is to target the α7 nicotinic acetylcholine receptor (nAChR), which is highly expressed in the hippocampus and contributes to the formation of long-term memory. In our previous study, we found that AVL-3288, a positive allosteric modulator of the α7 nAChR, improved cognitive recovery in rats after moderate fluid-percussion injury (FPI). However, whether AVL-3288 improved cognitive recovery specifically through the α7 nAChR was not definitively determined. In this study we utilized Chrna7 knockout mice and compared their recovery to wild-type mice treated with AVL-3288 after TBI. We hypothesized that AVL-3288 treatment would improve learning and memory in wild-type mice, but not Chrna7 mice after TBI. Adult male C57BL/6 wild-type and Chrna7 mice received sham surgery or moderate controlled cortical impact (CCI) and recovered for 3 months. Mice were then treated with vehicle or AVL-3288 at 30 min prior to contextual fear conditioning. At 3 months after CCI, expression of α7 nAChR, choline acetyltransferase (ChAT), high-affinity choline transporter (ChT), and vesicular acetylcholine transporter (VAChT) were found to be significantly decreased in the hippocampus. Treatment of wild-type mice at 3 months after CCI with AVL-3288 significantly improved cue and contextual fear conditioning, whereas no beneficial effects were observed in Chrna7 mice. Parietal cortex and hippocampal atrophy were not improved with AVL-3288 treatment in either wild-type or Chrna7 mice. Our results indicate that AVL-3288 improves cognition during the chronic recovery phase of TBI through modulation of the α7 nAChR.
创伤性脑损伤（TBI）会导致海马体内发生多种病理变化，从而对学习和记忆产生不良影响。目前，增强 TBI 后学习和记忆的治疗策略仍处于临床开发的早期阶段。一种策略是针对α7 烟碱型乙酰胆碱受体（nAChR），该受体在海马体中高度表达，有助于长时记忆的形成。在我们之前的研究中，我们发现α7 nAChR 的正变构调节剂 AVL-3288 可改善中度液压冲击伤（FPI）后大鼠的认知恢复。然而，AVL-3288 是否通过α7 nAChR 特异性改善认知恢复尚不确定。在这项研究中，我们利用 Chrna7 敲除小鼠，并比较它们在 TBI 后接受 AVL-3288 治疗的恢复情况与野生型小鼠的恢复情况。我们假设 AVL-3288 治疗会改善野生型小鼠的学习和记忆，但不会改善 Chrna7 小鼠的学习和记忆。成年雄性 C57BL/6 野生型和 Chrna7 小鼠接受假手术或中度皮质控制撞击（CCI），并恢复 3 个月。然后，在情景恐惧条件反射之前 30 分钟，用载体或 AVL-3288 处理小鼠。在 CCI 后 3 个月，发现海马体内α7 nAChR、胆碱乙酰转移酶（ChAT）、高亲和力胆碱转运体（ChT）和囊泡乙酰胆碱转运体（VAChT）的表达明显降低。在 CCI 后 3 个月，用 AVL-3288 治疗野生型小鼠可显著改善线索和情景恐惧条件反射，而 Chrna7 小鼠则无明显益处。AVL-3288 治疗并未改善野生型或 Chrna7 小鼠的顶叶皮层和海马体萎缩。我们的结果表明，AVL-3288 通过调节α7 nAChR 改善 TBI 慢性恢复期的认知。
