Interaction of serotonin transporter and TGFB1 facilitates histone serotonylation-mediated synaptic plasticity following environmental enrichment in stressed mouse Mus booduga

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 Mus booduga were assessed for a series of behaviours (direct wild, DW, n = 10); another group of mice was placed in SI for 10 days and then divided into three groups as follows: Animals were housed (i) short-term at standard conditions (STSC, n = 10) for 7 days, (ii) long-term at standard conditions (LTSC, n = 10) for 30 days, or (iii) environmental enriched (EE, n = 15) cage for 30 days. After behavioural analysis, the hippocampus region was dissected for further analysis. 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 (Bdnf) promoter and fine-tuned BDNF expression. Co-immunoprecipitation analysis showed enhanced interaction between SERT and TGFB1. Furthermore, two-dimensional gel-based western blot analysis revealed that SI-induced stress triggered immature- glycosylation of SERT (detected at 60 kDa, pI: 5.87) in STSC and EE mice. We observed an interaction between mature SERT and TGFB1 ( 152 kDa, pI: 7.831) in DW and EE mice. 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.