Droguerre Marine, Duchêne Adeline, Picoli Christèle, Portal Benjamin, Lejards Camille, Guiard Bruno P, Meunier Johann, Villard Vanessa, Déglon Nicole, Hamon Michel, Mouthon Franck, Charvériat Mathieu
Theranexus, Lyon, France.
Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), CNRS, UPS, Université de Toulouse, Toulouse, France.
Front Neurosci. 2020 Jun 16;14:563. doi: 10.3389/fnins.2020.00563. eCollection 2020.
Donepezil (DPZ) is an acetylcholinesterase inhibitor used in Alzheimer's disease to restore cognitive functions but is endowed with limited efficacy. Recent studies pointed out the implication of astroglial networks in cognitive processes, notably via astrocyte connexins (Cxs), proteins involved in gap junction intercellular communications. Hence, we investigated the impact on cognition of pharmacological or genetic modulations of those astrocyte Cxs during DPZ challenge in two rodent models of Alzheimer's disease-like memory deficits. We demonstrated that the Cx modulator mefloquine (MEF) significantly enhanced the procognitive effect of DPZ in both models. In parallel, we determined that MEF potentiated DPZ-induced release of acetylcholine in hippocampus. Finally, local genetic silencing of astrocyte Cxs in the hippocampus was also found to enhance the procognitive effect of DPZ, pointing out the importance of Cx-dependent astrocyte networks in memory processes.
多奈哌齐（DPZ）是一种用于治疗阿尔茨海默病以恢复认知功能的乙酰胆碱酯酶抑制剂，但其疗效有限。最近的研究指出星形胶质细胞网络在认知过程中的作用，特别是通过星形胶质细胞连接蛋白（Cxs），这些蛋白参与间隙连接细胞间通讯。因此，我们在两种类似阿尔茨海默病记忆缺陷的啮齿动物模型中，研究了在DPZ激发过程中对这些星形胶质细胞Cxs进行药理学或基因调控对认知的影响。我们证明，在两种模型中，Cx调节剂甲氟喹（MEF）显著增强了DPZ的促认知作用。同时，我们确定MEF增强了DPZ诱导的海马中乙酰胆碱的释放。最后，还发现海马中星形胶质细胞Cxs的局部基因沉默也增强了DPZ的促认知作用，指出依赖Cx的星形胶质细胞网络在记忆过程中的重要性。
