Long-term environmental enrichment prevents schizophrenia-like abnormalities and promotes hippocampal Slc6a4 gene demethylation in mice submitted to a two-hit model

Abstract

In the last decades, attention has been called to the need for preventive strategies against neurodevelopmental disorders. In the present study, we aimed to investigate the impacts of long-term environmental enrichment (EE) in preventing behavioral, neurochemical, and epigenetic changes in mice exposed to the two-hit model of schizophrenia. To this end, we used neonatal Swiss mice exposed to the viral mimetic polyinosinic:polycytidylic acid (PolyI:C) as first-hit on postnatal days (PND) 5–7 or sterile saline (zero-hit). On PND21, mice were randomly allocated to cages with standard (SE) or enriched environment (EE). From PND35-44, PolyI:C group was exposed to unpredictable stressors as second-hit. On PND70, after EE's last exposure, the animals underwent behavioral testing, and the hippocampus was collected for biochemical (Iba-1 and DCX) and epigenetic (SLC6A4 gene) analysis. The results showed that fifty days of EE exposure to two-hit mice, i.e., from infancy to adulthood, prevented sensorimotor gating deficits and working memory impairment while improving locomotor and exploratory activity. Furthermore, EE prevented hippocampal Iba-1 increased expression. EE-exposed mice presented increased hippocampal DCX expression. In addition, hippocampal demethylation of the SLC6A4 gene (serotonin transporter), an epigenetic reprogramming mechanism, was observed in the two-hit group submitted to EE. Our results reveal the preventive effects of long-term EE in mice exposed to the two-hit model of schizophrenia by mechanisms related to increased neurogenesis, reduced microglia reactivity, and epigenetic regulation of serotonergic signaling.