Serotonin triggers a transient epigenetic mechanism that reinstates adult visual cortex plasticity in rats

Abstract

Cortical circuitries are highly sensitive to experience during early life but this phase of heightened plasticity decreases with development. We recently demonstrated that fluoxetine reinstates a juvenile-like form of plasticity in the adult visual system. Here we explored cellular and molecular mechanisms that underlie the occurrence of these plastic phenomena. Adult rats were intracortically treated with serotonin (5-HT) whereas long-term fluoxetine-treated rats were infused with the 5-HT(1A) -receptor antagonist WAY-100635, brain-derived neurotrophic factor (BDNF) scavenger trkB-IgG or the mitogen-activated protein kinase inhibitor U0126. Plasticity was assessed as variations of visual cortex responsiveness after unilateral eyelid suture and reverse occlusion by using an electrophysiological approach. Real-time PCR and chromatin immunoprecipitation analysis were then used to explore alterations in gene expression and modifications of chromatin structure associated with the plastic outcome caused by fluoxetine in the visual system. Local infusion of 5-HT into visual cortex restored susceptibility to monocular deprivation in adulthood whereas infusion of WAY-100635, trkB-IgG or U0126 prevented the process of plasticity reactivation in fluoxetine-treated animals. Long-term fluoxetine treatment promoted a transient increase of Bdnf expression in the visual cortex, which was paralleled by an increased histone acetylation status at Bdnf promoter regions and by decreased expression of Hdac5. Accordingly, enhancing histone acetylation levels by systemic treatment with Trichostatin-A reactivated plasticity in the adult while WAY-100635-infusion prevented epigenetic modifications in Bdnf promoter areas. The data suggest a key role for 5-HT(1A) receptor and BDNF-trkB signalling in driving a transitory epigenetic remodelling of chromatin structure that underlies the reactivation of plasticity in the visual system.