Opposing roles of serotonin and neuropeptide FMRFamide in the regulation of epigenetic processes involved in the long-term memory formation

Abstract

The epigenetic modifications of histones have been studied intensively to understand the mechanisms of long-term memory. Previously, we have shown that histone H3 methylation at the activation (H3K4me3) and inhibition (H3K9me2) sites plays an important role in the formation of the defense reflex of food aversion in the mollusk Helix lucorum. It was suggested that these epigenetic modifications are controlled by the activation and inhibitory pathways involved in the long-term memory formation. Serotonin is a key activating mediator of the central nervous system in the formation of defensive reflexes in mollusks and neuropeptide FMRFamide is a key inhibitory mediator. Incubation of the central nervous system with these molecules models sensitization and habituation, respectively. Both these processes are involved in the formation of long-term memory. Due to the opposing roles of serotonin and FMRFamide in the plasticity of defense reflexes, we carried out a comparative study on the impact of these neurotransmitters on methylation of histone H3 in functionally different ganglia of the central nervous system of the Helix. It was shown that serotonin and FMRFamide have a reciprocal effect on histone H3 methylation in the subesophageal complex of ganglia, which specializes in defensive behavior. Thus, incubation of the Helix CNS with serotonin induces methylation of histone H3 for the activator (H3K4me3) and inhibitory (H3K9me2) sites, whereas incubation with FMRFamide reduces methylation at the both sites. A different pattern of histone H3 methylation was observed in the cerebral ganglia, which are involved in the signal processing of food stimuli. Incubation of the CNS with serotonin did not influence histone H3 methylation for the activator site and reduced methylation for the inhibitory one, while FMRFamide had no effect on histone H3 methylation. The obtained data indicate that the activation and inhibitory pathways mediated by serotonin and FMRFamide are capable of interacting at the epigenetic level through the influence on histone H3 methylation. These epigenetic changes may underlie the convergence of the activator and inhibitory pathways involved in the formation of long-term memory and affect the expression of genes required for plastic rearrangements.