Bijata Monika, Labus Josephine, Guseva Daria, Stawarski Michał, Butzlaff Malte, Dzwonek Joanna, Schneeberg Jenny, Böhm Katrin, Michaluk Piotr, Rusakov Dmitri A, Dityatev Alexander, Wilczyński Grzegorz, Wlodarczyk Jakub, Ponimaskin Evgeni
Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology of the Polish Academy of Science, Pasteura 3, Warsaw 02-093, Poland.
Cellular Neurophysiology, Center of Physiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
Cell Rep. 2017 May 30;19(9):1767-1782. doi: 10.1016/j.celrep.2017.05.023.
Rewiring of synaptic circuitry pertinent to memory formation has been associated with morphological changes in dendritic spines and with extracellular matrix (ECM) remodeling. Here, we mechanistically link these processes by uncovering a signaling pathway involving the serotonin 5-HT7 receptor (5-HT7R), matrix metalloproteinase 9 (MMP-9), the hyaluronan receptor CD44, and the small GTPase Cdc42. We highlight a physical interaction between 5-HT7R and CD44 (identified as an MMP-9 substrate in neurons) and find that 5-HT7R stimulation increases local MMP-9 activity, triggering dendritic spine remodeling, synaptic pruning, and impairment of long-term potentiation (LTP). The underlying molecular machinery involves 5-HT7R-mediated activation of MMP-9, which leads to CD44 cleavage followed by Cdc42 activation. One important physiological consequence of this interaction includes an increase in neuronal outgrowth and elongation of dendritic spines, which might have a positive effect on complex neuronal processes (e.g., reversal learning and neuronal regeneration).
与记忆形成相关的突触回路重塑与树突棘的形态变化以及细胞外基质（ECM）重塑有关。在这里，我们通过揭示一条涉及血清素5-HT7受体（5-HT7R）、基质金属蛋白酶9（MMP-9）、透明质酸受体CD44和小GTP酶Cdc42的信号通路，从机制上把这些过程联系起来。我们强调了5-HT7R与CD44（在神经元中被鉴定为MMP-9的底物）之间的物理相互作用，并发现5-HT7R刺激会增加局部MMP-9活性，引发树突棘重塑、突触修剪和长时程增强（LTP）受损。潜在的分子机制涉及5-HT7R介导的MMP-9激活，这会导致CD44裂解，随后激活Cdc42。这种相互作用的一个重要生理后果包括神经元生长增加和树突棘伸长，这可能对复杂的神经元过程（如逆向学习和神经元再生）产生积极影响。
