Seo, Jiyeon Hwang, Hongik Sohn, Heesung CHO, EUNSIL Jung, Sunmin KIM SOOHYUN Seung-Min Um Ji Yeon Kim Muwon Kang Choi, Yuri Jong-Hwan Kim Mirang Kim Seon-Young Kim Sun-Kyung Lee Joohong Ahnn Rhim, Hyewhon Dong-Gyu Jo Eunjoon Kim Park, Mikyoung 2024-01-12T02:31:55Z 2024-01-12T02:31:55Z 2022-11-23 2023-03 1359-4184 https://pubs.kist.re.kr/handle/201004/75789 Spatial learning and memory flexibility are known to require long-term potentiation (LTP) and long-term depression (LTD), respectively, on a cellular basis. We previously showed that cyclin Y (CCNY), a synapse-remodeling cyclin, is a novel actin-binding protein and an inhibitory regulator of functional and structural LTP in vitro. In this study, we report that Ccny knockout (KO) mice exhibit enhanced LTP and weak LTD at Schaffer collateral-CA1 synapses in the hippocampus. In accordance with enhanced LTP, Ccny KO mice showed improved spatial learning and memory. However, although previous studies reported that normal LTD is necessary for memory flexibility, Ccny KO mice intriguingly showed improved memory flexibility, suggesting that weak LTD could exert memory flexibility when combined with enhanced LTP. At the molecular level, CCNY modulated spatial learning and memory flexibility by distinctively affecting the cofilin-actin signaling pathway in the hippocampus. Specifically, CCNY inhibited cofilin activation by original learning, but reversed such inhibition by reversal learning. Furthermore, viral-mediated overexpression of a phosphomimetic cofilin-S3E in hippocampal CA1 regions enhanced LTP, weakened LTD, and improved spatial learning and memory flexibility, thus mirroring the phenotype of Ccny KO mice. In contrast, the overexpression of a non-phosphorylatable cofilin-S3A in hippocampal CA1 regions of Ccny KO mice reversed the synaptic plasticity, spatial learning, and memory flexibility phenotypes observed in Ccny KO mice. Altogether, our findings demonstrate that LTP and LTD cooperatively regulate memory flexibility. Moreover, CCNY suppresses LTP while facilitating LTD in the hippocampus and negatively regulates spatial learning and memory flexibility through the control of cofilin-actin signaling, proposing CCNY as a learning regulator modulating both memorizing and forgetting processes. English Nature Publishing Group Cyclin Y regulates spatial learning and memory flexibility through distinct control of the actin pathway Article 10.1038/s41380-022-01877-0 1 Molecular Psychiatry, v.28, pp.1351 - 1364 Molecular Psychiatry 28 1351 1364 N scie scopus 000888700100001 Biochemistry & Molecular Biology Neurosciences Psychiatry Biochemistry & Molecular Biology Neurosciences & Neurology Psychiatry Article; Early Access LONG-TERM DEPRESSION DENDRITIC SPINE SYNAPTIC PLASTICITY COGNITIVE FLEXIBILITY POTENTIATION CONSOLIDATION RHO TRAFFICKING RECOGNITION MORPHOLOGY