Therapeutic Inhibition of MicroRNA‐124‐3p Induces Histone Modification Changes in the Hippocampus in a Rat Model of Gulf War Illness

Abstract

Gulf War Illness (GWI) is a chronic, multisymptomillness that continues to affect 30% of the 700,000 US veterans deployed to the Persian Gulf during the 1990–1991 Gulf War. Memory dysfunction and depression are common symptoms. Epidemiological studies have consistently identified neurotoxic chemical exposures as the strongest risk factors for GWI, but after 28 years, useful treatments are lacking and underlying cellular and molecular mechanisms involved in its pathobiology remain poorly understood. Using an established rat model of GWI, we previously identified chronic elevation of microRNA‐124‐3p(miR‐124) levels in the hippocampus whose gene targets are involved in cognition‐associated pathways and neuroendocrine function. We further showed that intracerebro ventricular (icv) infusion of locked nucleic acid (LNA)‐miR‐124 inhibitor increased hippocampal expression of downstream target genes important for synaptic plasticity, glucocorticoid signaling, and neurogenesis compared to LNA‐scrambled oligonucleotide, suggesting that miR‐124 inhibition may be a promising therapeutic approach to improve cognition and neuroendocrine dysfunction in GWI. This strategy has also been proposed to improve memory deficits and/or depression in patients with multiple sclerosis, major depressive disorder, amyotrophic lateral sclerosis, and Alzheimer's disease. Because histone post‐translational modifications are critical for gene expression during memory processes, the aim of this study was to determine whether miR‐124 inhibition alters histone modifications in the hippocampus of GWI rats. Nine months after a 28‐day exposure regimen of GW chemicals and stress, rats underwent icv infusion of LNA‐miR‐124 inhibitor or LNA‐scrambled control from implanted osmotic pumps delivering 0.1 nmol/day for 28 days (n=5 per group). Hippocampi were harvested and underwent extraction of histones. Targeted analysis of >80 unmodified and modified histone peptides was performed in triplicate using mass spectrometry (Active Motif). LNA‐miR‐124 inhibitor induced 11 histone modification changes, with histone H3 methylationat lysine (K) residues 18, 27, 36, and 79 being the most predominant changes observed. These included a 22% decrease (p<0.001) in H3K27me3, a marker of gene repression known to be elevated in neuro degenerative diseases and during aging, and a 20% increase (p=0.008) in H3K36me3, a marker of transcriptional activation known to increase during object recognition memory and decrease during aging. Results suggest that miR‐124 inhibition induces histone modifications in the hippocampus that likely correspond with enhanced transcription of genes important for synaptic plasticity and neuroendocrine signaling shown previously to occur in GWI rats treated with LNA‐miR‐124 inhibitor. Future work is needed to identify the transcriptional targets of these histone markers to better understand the potential therapeutic benefits of miR‐124inhibition for GWI and other cognitive disorders.Support or Funding InformationDoD CDMRP Gulf War Illness Research Program grant award GW150132. Content is that of the authors and does not reflect the official policy or position of the Department of the Army, Department of Defense, or the US government.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.