Aging Triggers a Repressive Chromatin State at Bdnf Promoters in Hippocampal Neurons

ERNEST PALOMER; ADRIÁN MARTÍN-SEGURA; SHISHIR BALIYAN; TARIQ AHMEND; DETLEF BALSCHUN; CÉSAR VENERO; MAURICIO MARTIN; CARLOS G DOTTI

Cell Reports

Cell Press

Año: 2016

Cognitive capacities decline during aging an event accompanied by the altered transcriptional regulation of synaptic activity controlled genes. In this work we show that the transcriptional induction of the Bdnf gene by a mnemonic stimulus is impaired in old hippocampal neurons. Mechanistically, this effect is due to the altered NMDA receptor-mediated activation of CaMKII, resulting in impaired displacement of the histone deacetylase 4 from specific Bdnf promoters, impaired recruitment of the histone acetyltransferase CBP, reduced H3K27 acetylation and reduced H3K27Me3 demethylation. In turn, altered NMDA-CaMKII signaling is due to the constitutive reduction of synaptic cholesterol that occurs with the normal aging. Consistently, poor NMDA-triggered Bdnf transcription and altered epigenetic remodeling were rescued by the increase of neuronal cholesterol in-vitro, ex-vivo and in-vivo in 20 month-old mice. Furthermore, in vivo prevention of the age-associated cholesterol reduction also rescued the electrophysiological and behavioral deficits typical of the old.