DNA Methylation Inhibition Reversibly Impairs the Long-Term Context Memory Maintenance in Helix.

This work aims to study the epigenetic mechanisms of regulating long-term context memory in the gastropod mollusk: Helix. We have shown that RG108, an inhibitor of DNA methyltransferase (DNMT), impaired long-term context memory in snails, and this impairment can be reversed within a limited time window: no more than 48 h. Research on the mechanisms through which the long-term context memory impaired by DNMT inhibition could be reinstated demonstrated that this effect depends on several biochemical mechanisms: nitric oxide synthesis, protein synthesis, and activity of the serotonergic system. Memory recovery did not occur if at least one of these mechanisms was impaired. The need for the joint synergic activity of several biochemical systems for a successful memory rescue confirms the assumption that the memory recovery process depends on the process of active reconsolidation, and is not simply a passive weakening of the effect of RG108 over time. Finally, we showed that the reactivation of the impaired memory by RG108, followed by administration of histone deacetylase inhibitor sodium butyrate, led to memory recovery only within a narrow time window: no more than 48 h after memory disruption.

Detailed Analysis of Dorsal-Ventral Gradients of Gene Expression in the Hippocampus of Adult Rats.

We performed RNA sequencing of the dorsal and ventral parts of the hippocampus and compared it with previously published data to determine the differences in the dorsoventral gradients of gene expression that may result from biological or technical variability. Our data suggest that the dorsal and ventral parts of the hippocampus differ in the expression of genes related to signaling pathways mediated by classical neurotransmitters (glutamate, GABA, monoamines, etc.) as well as peptide and Wnt ligands. These hippocampal parts also diverge in the expression of axon-guiding molecules (both receptors and ligands) and splice isoforms of genes associated with intercellular signaling and cell adhesion. Furthermore, analysis of differential expressions of genes specific for astrocytes, microglia, oligodendrocytes, and vascular cells suggests that non-neuronal cells may also differ in the characteristics between hippocampal parts. Analysis of expression of transposable elements showed that depletion of ribosomal RNA strongly increased the representation of transposable elements in the RNA libraries and helped to detect a weak predominance of expression of these elements in the ventral hippocampus. Our data revealed new molecular dimensions of functional differences between the dorsal and ventral hippocampus and points to possible cascades that may be involved in the longitudinal organization of the hippocampus.

Sodium butyrate as a selective cognitive enhancer for weak or impaired memory.

Several recent studies showed that memory can be modulated by manipulating chromatin modifications using histone deacetylase (HDAC) inhibitors during memory formation, consolidation, and reconsolidation. We used a context fear conditioning paradigm with minimal non-painful current as a reinforcement, what elicited alertness to the context and freezing during tests in rats. Such paradigm resulted in a relatively weak memory in significant part of the rats. Here, we demonstrate that intraperitoneal administration of the HDAC inhibitor sodium butyrate immediately following memory reactivation, produced memory enhancement in rats with weak memory, however, not in rats with strong memory. Additionally, we investigated the ability of the HDAC inhibitor sodium butyrate to restore the contextual memory impaired due to the blockade of protein synthesis during memory reactivation. The results obtained evidence that the HDAC inhibitor sodium butyrate reinstated the impaired contextual memory. This enhancement effect is consistent with other studies demonstrating a role for HDAC inhibitors in the facilitation of contextual fear.