Epigenetic mechanisms involved in neuronal Bdnf gene expression in adult and aged mouse in response to cognitive stimulation

Resumen

Transcription of immediate early memory genes is an essential process in brain function, regulating, among other processes, synaptic plasticity. It is well established the necessity of gene transcription in order to maintain the late phases of the long-term potentiation (LTP) and the long-term depression (LTD). Several works performed in animals subjected to different memory paradigms have shown that there are epigenetic mechanisms involved in memory genes regulation. However, little is known about the contribution of these epigenetics mechanisms in response to a single stimulus, in the adult and in the old brain. The aim of this thesis was to characterise such mechanisms in response to LTD, in order to better understand the regulation of Bdnf gene expression, and its possible relation with the aged associated learning and memory deficits. In this thesis we present that LTD stimulation triggered by low NMDA dose in young adult animals, induces the transcription of Bdnf gene from promoters I, II, IV and VI by H3K27Me3 demethylation and H3K27Me3 phosphorylation at Serine 28, leading to displacement of EZH2, the catalytic subunit of Polycomb Repressor Complex 2. LTD not only does induce EZH2 repressor detachment, but also the dissociation of another transcriptionally repressive enzyme such as histone deacetylase 4 (HDAC4). We also show that LTD enhances acetylation of histone H3K27 via pCREB/CBP. Differently from the described situation, typical of the mature brain, we present data showing that the normal singling transduction of the young upon LTD is impaired in the aged hippocampus, leading to a different basal chromatin state at Bdnf promoters in the old. The consequence of this impairment is the loss of Bdnf induction in the old when exposed to LTD, as a result of impaired HDAC4 dissociation, CBP recruitment and Histone H3K27 acetylation at Bdnf promoters. We also have observed that the loss of cholesterol at the neuronal plasma membrane, a physiological feature of the old, plays a role in these epigenetic deficits. In fact, cholesterol addition to old hippocampal slices rescued Bdnf epigenetic regulation and expression in response to LTD. Furthermore, cholesterol reduction in young adult hippocampal slices led to similar deficits to the ones found in the old animals. In further support of the cholesterol loss-epigenetic dysregulation in the old, oral administration of Voriconazole, an inhibitor of the enzyme responsible for cerebral cholesterol loss (Cyp46A1), rescued hippocampal cholesterol loss and enhanced cognitive abilities in the old animals, improving Bdnf epigenetic regulation and expression in response to LTD. These results unveil one of the mechanisms involved in the cognitive decline of the old and propose Cyp46A1 as valuable therapeutic possibility.