Along with neuronal mechanisms devoted to memory consolidation –including long term potentiation of synaptic strength as prominent electrophysiological correlate, and inherent dendritic spines stabilization as structural counterpart– negative control of memory formation and synaptic plasticity has been described at the molecular and behavioral level. Within this work, we report a role for the epigenetic corepressor Lysine Specific Demethylase 1 (LSD1) as a negative neuroplastic factor whose stress-enhanced activity may participate in coping with adverse experiences. Constitutively increasing LSD1 activity via knocking out its dominant negative splicing isoform neuroLSD1 (neuroLSD1^KO mice), we observed extensive structural, functional and behavioral signs of excitatory decay, including disrupted memory consolidation. A similar LSD1 increase, obtained with acute antisense oligonucleotide-mediated neuroLSD1 splicing knock down in primary neuronal cultures, dampens spontaneous glutamatergic transmission, reducing mEPSCs. Remarkably, LSD1 physiological increase occurs in response to psychosocial stress-induced glutamatergic signaling. Since this mechanism entails neuroLSD1 splicing downregulation, we conclude that LSD1/neuroLSD1 ratio modulation in the hippocampus is instrumental to a negative homeostatic feedback, restraining glutamatergic neuroplasticity in response to glutamate. The active process of forgetting provides memories with salience. With our work, we propose that softening memory traces of adversities could further represent a stress-coping process in which LSD1/neuroLSD1 ratio modulation may help preserving healthy emotional references.

伴随着致力于记忆巩固的神经机制-包括突触强度的长期增强（作为突出的电生理相关性）和固有的树突棘稳定作为结构的对应物-在分子和行为水平上已经描述了记忆形成和突触可塑性的负控制。在这项工作中，我们报告了表观遗传共抑制物赖氨酸特异性脱甲基酶1（LSD1）作为负性神经增生因子的作用，其压力增强活性可能参与应对不良经历。通过敲除LSD1的显性负剪接亚型NeuroLSD1（neuroLSD1 ^KO小鼠），我们观察到了兴奋性衰退的广泛结构，功能和行为体征，包括破坏的记忆巩固。急性反义寡核苷酸介导的NeuroLSD1剪接在原代神经元培养物中获得的类似LSD1增加，抑制了自发性谷氨酸能传递，降低了mEPSC。值得注意的是，LSD1的生理反应是由于社会心理压力引起的谷氨酸能信号传导而发生的。由于这种机制需要神经LSD1剪接下调，因此我们得出结论，海马中LSD1 / neuroLSD1比例调节对负稳态反馈有帮助，从而抑制了谷氨酸对谷氨酸能神经可塑性的作用。积极的忘记过程为记忆提供了显着性。通过我们的工作