Orfila James E, Dietz Robert M, Schroeder Christian, Patsos Olivia P, Burch Amelia, Bahamonde Kiara E, Coakley Kelley A, Carter Danelle J, Clevenger Amy C, Hendry-Hofer Tara B, Le Tuan D, Maddry Joseph K, Schauer Steven G, Bebarta Vikhyat S, Herson Paco S
Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, OH, United States.
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States.
Front Synaptic Neurosci. 2025 Apr 25;17:1534379. doi: 10.3389/fnsyn.2025.1534379. eCollection 2025.
Traumatic Brain Injury (TBI) is a leading cause of mortality and morbidity in adults and can lead to long-term disability, including cognitive and motor deficits. Despite advances in research, there are currently no pharmacological interventions to improve outcomes after TBI. Studies suggest that non-selective transient receptor potential melastatin 2 (TRPM2) channels contribute to brain injury in models of ischemia, however TRPM2 remains understudied following TBI. Thus, we utilized TRPM2 KO mice and a novel TRPM2 inhibiting peptide, tatM2NX, to assess the role of TRPM2 in TBI-induced injury and functional recovery. This study used histological analysis of injury, neurobehavior and electrophysiology to assess the role of TRPM2 on injury and cognitive recovery (memory) impairments using the controlled cortical impact (CCI) model to induce TBI in mice. Histological analysis used to investigate brain injury volume at 7 days after TBI showed sex differences in response to injury in TRPM2 KO mice but no pharmacological effects in our WT mice. A contextual fear-conditioning task was used to study memory function 7 or 30 days after TBI and demonstrates that sham-operated mice exhibited significant freezing behavior compared to TBI-operated mice, indicating impaired memory function. Mice administered tat-M2NX 2 h after TBI exhibited a significant reduction of freezing behavior compared to control tat-scrambled (tat-SCR)-treated mice, suggesting improvement in memory function after TBI. To test the effect of TBI on hippocampal long-term potentiation (LTP), a well-established cellular model of synaptic plasticity associated with changes in learning and memory, extracellular field recordings of CA1 neurons were performed in hippocampal slices prepared 7 days after TBI. Consistent with our behavioral testing, we observed impaired hippocampal LTP in mice following TBI (tat-SCR), compared to sham control mice. However, mice treated with tat-M2NX after TBI exhibited preserved LTP, consistent with the improved memory function observed in our behavioral studies. While this data implicates TRPM2 in brain pathology following TBI, the improvement in memory function without providing histological protection suggests that administration of tatM2NX at an acute time point differentially affects hippocampal regions compared to cortical regions.
创伤性脑损伤（TBI）是成人死亡和发病的主要原因，可导致长期残疾，包括认知和运动功能障碍。尽管研究取得了进展，但目前尚无改善TBI后预后的药物干预措施。研究表明，非选择性瞬时受体电位褪黑素2（TRPM2）通道在缺血模型中导致脑损伤，然而，TBI后TRPM2仍未得到充分研究。因此，我们利用TRPM2基因敲除小鼠和一种新型的TRPM2抑制肽tatM2NX，来评估TRPM2在TBI诱导的损伤和功能恢复中的作用。本研究使用损伤的组织学分析、神经行为学和电生理学，通过控制皮质撞击（CCI）模型在小鼠中诱导TBI，来评估TRPM2对损伤和认知恢复（记忆）障碍的作用。用于研究TBI后7天脑损伤体积的组织学分析显示，TRPM2基因敲除小鼠对损伤的反应存在性别差异，但在野生型小鼠中未观察到药物作用。采用情境恐惧条件反射任务研究TBI后7天或30天的记忆功能，结果表明，与TBI手术小鼠相比，假手术小鼠表现出显著的僵住行为，表明记忆功能受损。TBI后2小时给予tat-M2NX的小鼠与对照tat-乱序肽（tat-SCR）处理的小鼠相比，僵住行为显著减少，提示TBI后记忆功能得到改善。为了测试TBI对海马体长期增强（LTP）的影响，LTP是一种与学习和记忆变化相关的成熟的突触可塑性细胞模型，在TBI后7天制备的海马体切片中对CA1神经元进行细胞外场记录。与我们的行为测试一致，我们观察到TBI（tat-SCR）小鼠的海马体LTP受损，与假手术对照小鼠相比。然而，TBI后用tat-M2NX处理的小鼠表现出保留的LTP，这与我们行为学研究中观察到的记忆功能改善一致。虽然这些数据表明TRPM2在TBI后的脑病理学中起作用，但记忆功能的改善而未提供组织学保护表明，与皮质区域相比，在急性时间点给予tatM2NX对海马体区域的影响不同。
