2. Academic Validation
  3. Social memory maintenance relies on social interaction-induced proteolytic products of neuroligin 1

Social memory maintenance relies on social interaction-induced proteolytic products of neuroligin 1

  • Signal Transduct Target Ther. 2025 Nov 24;10(1):387. doi: 10.1038/s41392-025-02467-6.
An Liu # 1 2,  Xingcan Li # 1 2,  Mei Zhuang 1 2,  Qiaoyun Ren 1 2,  Jinglei Zhang 1 2,  Dandan Lv 1 2,  Miao Wu 1 2,  Xingjie Bian 1 2,  Chengyan Zhu 1 2,  Xiuqi Yang 1 2,  Moyi Li 1 2,  Yanan Wang 1 2,  Zhengping Jia 3 4 5,  Wei Xie 6 7 8
Affiliations

Affiliations

  • 1 The Key Laboratory of Developmental Genes and Human Disease, The School of Life Science and Technology, Southeast University, Nanjing, China.
  • 2 Institute for Brain and Intelligence, Southeast University, Nanjing, China.
  • 3 The Key Laboratory of Developmental Genes and Human Disease, The School of Life Science and Technology, Southeast University, Nanjing, China. [email protected].
  • 4 Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
  • 5 Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. [email protected].
  • 6 The Key Laboratory of Developmental Genes and Human Disease, The School of Life Science and Technology, Southeast University, Nanjing, China. [email protected].
  • 7 Institute for Brain and Intelligence, Southeast University, Nanjing, China. [email protected].
  • 8 Jiangsu Co-innovation Center of Neuroregeneration, Southeast University, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 41276544 DOI: 10.1038/s41392-025-02467-6
Abstract

Proper social behaviors are essential for survival and success, and deficits in these behaviors are associated with many brain disorders. However, the mechanisms underlying the formation and maintenance of social memory remain poorly understood. In this study, we demonstrate that social interaction with unfamiliar mouse induces α- and γ-secretase-dependent proteolysis of Neuroligin 1 (NLG1) in the ventral hippocampus (vHPC). The intracellular hydrolysate fragment, NLG1-CTD, regulates synaptic plasticity, spine strengthening, and the maintenance of social memory through its PDZ binding domain (PBD) and the cofilin signaling pathway. Both γ-secretase inhibition and deletion of the secretase recognition site on NLG1 prevent cofilin phosphorylation and impair the maintenance of social memory by inhibiting the production of NLG1-CTD. Injection of the Tat-PBD peptide into the vHPC inhibits cofilin activity and rescues deficits in social memory maintenance in mouse models. Additionally, our findings indicate that deficits in maintaining memory for sequentially presented social objects within a short temporal interval may be associated with insufficient levels of NLG1-CTD. Supplementation of Tat-PBD into the vHPC promotes maturation of dendritic spines and restores the maintenance of memory for the second social object. We also discovered that NLG1-CTD/PBD may play a role in maintaining novel object recognition memory. In summary, this work uncovers a novel mechanism that links extracellular and intracellular signal transduction processes to synaptic remodeling during learning and memory maintenance, providing a systematic perspective that connects memory formation, maintenance, and synaptic structural and functional plasticity.

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