Disruption of Cdk5-GluN2B complex by a small interfering peptide attenuates social isolation-induced escalated intermale attack behavior and hippocampal oxidative stress in mice

• Published in: Free radical biology & medicine 2024-01, Vol.210, p.54-64
• Main Authors: Ai, Heng, Li, Minghao, Fang, Weiqing, Wang, Xuemeng, Liu, Xinxin, Wu, Lihui, Zhang, Bin, Lu, Wen
• Format: Article
• Language: English
• Subjects: Aggression; Aggression - physiology; Animals; Attack behavior; Cyclin-dependent kinase 5; Hippocampus; Humans; Mice; N-Methyl-d-aspartate receptor; Oxidative stress; Pandemics; Peptides - pharmacology; Social Isolation
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2023.11.006

Social isolation has emerged as a significant issue during the COVID-19 pandemic that can adversely impact human mental health and potentially lead to pathological aggression. Given the lack of effective therapeutic interventions for aggressive behavior, alternative approaches are necessary. In this study, we utilized a genetic method combined with a pharmacological approach to identify and demonstrate the crucial role of Cdk5 in escalated intermale attack behavior induced by 2-week social isolation. Moreover, we developed a small peptide that effectively disrupts the interaction between Cdk5 and GluN2B, given the known involvement of this complex in various neuropsychiatric disorders. Administration of the peptide, either systemically or via intrahippocampal injection, significantly reduced oxidative stress in the hippocampus and attenuated intermale attack behavior induced by 2-week social isolation. These findings highlight the previously unknown role of the hippocampal Cdk5-GluN2B complex in social isolation-induced aggressive behavior in mice and propose the peptide as a promising therapeutic strategy for regulating attack behavior and oxidative stress. [Display omitted] •Pharmacological blockade or genetic ablation of Cdk5 nullifies social isolation (SI)-induced escalated attack behavior.•A small TAT peptide designed to disrupt the Cdk5/GluN2B complex, prevents SI-induced increased attack behavior.•The small TAT peptide suppresses oxidative stress in the hippocampus of SI mice.