Nicole Mons et al. dans Hippocampus

Les inhibiteurs d'histone deacetylases sont-ils toujours bénéfiques pour la mémoire ?

Le 28 janvier 2015

Post-training, intra-hippocampal HDAC inhibition differentially impacts neural circuits underlying spatial memory in adult and aged mice. Dagnas M, Micheau J, Decorte L, Beracochea D, Mons N. Hippocampus. 2014 Dec 19. doi: 10.1002/hipo.22406.

Although studies of memory formation and consolidation have emphasized the importance of multiple intracellular signaling cascades and transcription factors,
it has become clear that epigenetic events play a critical role throughout the modulation of plasticity/memory-related gene expression. Of the various epigenetic modifications, the acetylation of histone proteins on their N-terminal tails via histone acetyltransferases has emerged as a transcriptionally permissive mark. This process causes chromatin structure to relax, leading to enhanced transcription, and can be reversed by histone deacetylases (HDACs). Pre-training treatments with HDAC inhibitors (HDACi) improve hippocampus-dependent learning and memory in young “healthy” rodents and ameliorate or restore memory functions in aged rodents as well as in different neurodegenerative models. Enhanced memory consolidation after post-training HDAC blockade was also observed in young rodents. However, whether such treatment is sufficient to prevent age-associated memory impairments remains largely unclear. In the present work, we demonstrate that post-training injection of nonselective HDACi trichostatin A (TSA) into the dorsal hippocampus improved long-term spatial memory in young-adults, but fails to rescue memory impairments in older mice.

Using a one-day massed spatial learning task in the water maze, we show that local, intra-hippocampal HDAC blockade in young mice induces histone hyperacetylation in the dorsal hippocampus together with an increase in the dorsomedial part of the striatum (DMS), a structure important for spatial information processing. Importantly, HDAC blockade completely reversed age-associated reduced histone acetylation in the dorsal hippocampus but failed to rescue altered histone acetylation in the DMS. Additionally, we show that intra-hippocampal HDAC blockade produced concomitant decreases (in young-adults) or increases (in older mice) of acetylated histone levels in structures critically involved in stress and emotional responses.

Taken altogether, these results highlight a key role for histone acetylation-deacetylation balance in the regulation of network plasticity during memory processes and further suggest that age-associated memory impairments may be related to an inability to recruit appropriate circuit-specific epigenetic patterns during consolidation processes.

Nicole Mons
Chargé de Recherches CNRS (CR1), HDR
Team: Interactions between emotions and memory systems: from normal to pathological aging. Daniel Beracochea
Domain: Cognition and behaviour / Animal cognition and behaviour

Nicole Mons

Dernière mise à jour le 29.01.2015