Interaction of serotonin transporter and TGFB1 facilitates histone serotonylation-mediated synaptic plasticity following environmental enrichment in stressed mouse Mus booduga.
📄 Abstract
Environmental enrichment (EE) has been used as a non-pharmacological intervention to facilitate neurotransmission and improve neurobehaviour. In this study, we examined whether EE improves learning and memory in mice subjected to social isolation (SI)-induced stress through serotonin (5-HT)-mediated histone modifications. Field-caught mice EE mice showed reduced SI-induced anxiety-like behaviour and improved learning and memory compared to STSC and LTSC mice. Furthermore, EE conferred resilience to SI-induced changes in the serotonergic system [e.g., levels of 5-HT; serotonin transporter (SERT); 5-HT3A receptor, and monoamine oxidase A] and facilitated the interaction with transforming growth factor-β1 (TGFB1). The SERT + TGFB1 complex further activated transglutaminase-2 and tryptophan-aspartic acid repeat-containing protein-5, enhances histone-3 lysine-4 trimethylation (H3K4me3), serotonylation of histone-3 glutamine-5 (H3Q5Ser), dual modification (i.e. H3K4me3Q5Ser), and reduced the activity of lysine-specific demethylase 1. Elevated levels of H3K4me3Q5Ser regulated methylation of the brain-derived neurotrophic factor ( Taken together, EE conferred resilience to SI-induced stress and enhanced SERT and TGFB1 interaction, which in turn facilitated the activation of the serotonergic system and histone serotonylation-mediated active transcription of BDNF. Consequently, EE mice exhibited reduced anxiety-like behaviours and improved learning and memory. The online version contains supplementary material available at 10.1186/s13072-025-00653-y.