Folate-mediated transgenerational inheritance of sperm DNA methylation patterns correlate with spinal axon regeneration.

In mammals, the molecular mechanisms underlying transgenerational inheritance of phenotypic traits in serial generations of progeny after ancestral environmental exposures, without variation in DNA sequence, remain elusive. We've recently described transmission of a beneficial trait in rats and mice, in which F0 supplementation of methyl donors, including folic acid, generates enhanced axon regeneration after sharp spinal cord injury in untreated F1 to F3 progeny linked to differential DNA methylation levels in spinal cord tissue. To test whether the transgenerational effect of folic acid is transmitted via the germline, we performed whole-genome methylation sequencing on sperm DNA from F0 mice treated with either folic acid or vehicle control, and their F1, F2, and F3 untreated progeny. Transgenerational differentially methylated regions (DMRs) are observed in each consecutive generation and distinguish folic acid from untreated lineages, predominate outside of CpG islands and in regions of the genome that regulate gene expression, including promoters, and overlap at both the differentially methylated position (DMP) and gene levels. These findings indicate that molecular changes between generations are caused by ancestral folate supplementation. In addition, 29,719 DMPs exhibit serial increases or decreases in DNA methylation levels in successive generations of untreated offspring, correlating with a serial increase in the phenotype across generations, consistent with a 'wash-in' effect. Sibship-specific DMPs annotate to genes that participate in axon- and synapse-related pathways.

Hippocampal cAMP regulates HCN channel function on two time scales with differential effects on animal behavior.

Hyperpolarization-activated cyclic nucleotide­gated (HCN) channels regulate neuronal excitability and represent a possible therapeutic target for major depressive disorder (MDD). These channels are regulated by intracellular cyclic adenosine monophosphate (cAMP). However, the relationship between cAMP signaling and the influence of HCN channels on behavior remains opaque. In this study, we investigated the role of hippocampal cAMP signaling on behavior using chemogenetic technology in mice. Acutely increasing cAMP limited spatial memory and motivated behavior by increasing HCN function. However, chronically elevated cAMP limited surface trafficking of HCN channels by disrupting the interaction between HCN and tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), an auxiliary subunit. Chronically increased cAMP in the dorsal hippocampus was also sufficient to rescue cognitive deficits induced by chronic stress in mice. These results reveal a behaviorally relevant form of regulation of HCN channel surface expression that has potential as a therapeutic target for cognitive deficits related to chronic stress.