Inhibition of histone lysine demethylase restores learning and memory in aged mice

Bhatt, S.; MacBean, L.; Kramar, E.; Perez-Sisques, L.; Smethurst, P.; Robb, J. L.; Jindal, N.; Fetterly, T.; Graham, A.; Wood, M.; Gillotin, S.; Giese, K. P.; Basson, M. A.

doi:10.64898/2025.12.22.695858

bioRxiv · 10.64898/2025.12.22.695858

Inhibition of histone lysine demethylase restores learning and memory in aged mice

Bhatt, S.·MacBean, L.·Kramar, E.·Perez-Sisques, L.·Smethurst, P.·Robb, J. L.·Jindal, N.·Fetterly, T.·Graham, A.·Wood, M.·Gillotin, S.·Giese, K. P.·Basson, M. A.

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Abstract

Chromatin undergoes dramatic changes during the ageing process. In the brain, these chromatin changes are thought to underlie age-associated deficits in the activity-dependent gene transcription necessary for memory consolidation. Here, we show that the levels of a specific histone post-translational modification (PTM), trimethylation of lysine 4 on histone 3 (H3K4me3) is markedly increased in the hippocampus of aged mice and that the activity-induced increase in H3K4me3 that is observed in response to a learning stimulus in young mice, is severely blunted in the aged hippocampus. H3K4me3 typically marks open, accessible chromatin at the transcriptional start sites (TSSs) of actively transcribed genes. We identify altered H3K4me3 peaks at TSSs and show that ca. 90% of the activity-induced H3K4me3 changes at TSSs are either absent or reduced in the aged hippocampus. To understand the biological significance of these age-associated changes, we screened a library of pharmacological compounds for compounds that can alter H3K4me3 levels in hippocampal neurons. We show that treatment of aged mice with one of these, the LSD1 inhibitor ORY-1001, restored normal learning and memory in object location and recognition tasks. Furthermore, we show that ORY-1001 treatment increased long-term potentiation (LTP), a form of synaptic plasticity deficient in the aged hippocampus. These findings suggest that targeting the epigenetic machinery that regulates activity-dependent gene transcription may represent an avenue for treating age-associated cognitive impairment. HighlightsO_LIH3K4me3 levels are elevated in the naive aged mouse hippocampus C_LIO_LIActivity-dependent H3K4me3 induction is impaired in the aged mouse hippocampus C_LIO_LILSD1 inhibition restores learning and memory in aged mice C_LIO_LILSD1 inhibition restores activity-dependent Arc induction and increases LTP in the aged hippocampus C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/695858v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@fccd92org.highwire.dtl.DTLVardef@11c4d93org.highwire.dtl.DTLVardef@128f8b8org.highwire.dtl.DTLVardef@e1341f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Bhatt, S., MacBean, L., Kramar, E., Perez-Sisques, L., Smethurst, P., Robb, J. L., Jindal, N., Fetterly, T., Graham, A., Wood, M., Gillotin, S., Giese, K. P., Basson, M. A.. 2025-12-23. Inhibition of histone lysine demethylase restores learning and memory in aged mice. https://doi.org/10.64898/2025.12.22.695858

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