INIMEC - CONICET   05467
INSTITUTO DE INVESTIGACION MEDICA MERCEDES Y MARTIN FERREYRA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Constitutive Hippocampal Cholesterol Loss Underlies Poor Cognition in Old Rodents: effect on receptor trafficking and in epigenetic mechanisms
Autor/es:
ERNEST PALOMER; CARLOS G DOTTI; MAURICIO GERARDO MARTÍN
Reunión:
Congreso; XXX Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2015
Resumen:
Cognitive decline is one of the many characteristics of aging. Reduced long-term potentiation (LTP) and long-term depression (LTD) are thought to be responsible for this decline, although the precise mechanisms underlying LTP and LTD dampening in the old remain unclear. We previously showed that aging is accompanied by the loss of cholesterol from the hippocampus, leading to PI3K/Akt phosphorylation which in turn perturbs the normal cellular and molecular responses induced by LTD. Electrophysiology recordings in brain slices of old mice and in anesthetized elderly rats demonstrate that the reduced hippocampal LTD associated with age can be rescued by cholesterol perfusion. Later, we found that a memory-inducing stimulus triggered by NMDA application induced the transcription of Bdnf promoters by H3K27Me3 demethylation and H3K27Me3 phosphorylation leading to displacement of EZH2, the catalytic subunit of Polycomb Repressor Complex 2. Our data also showed that the fast transient expression of Bdnf promoters after neuronal stimulation is dependent on acetylation of histone H3K27 by CREB/pCBP complex. Interestingly, these epigenetic mechanisms controlling Bdnf induction are impaired in old neurons and rescued by cholesterol replenishment. Accordingly, cholesterol replenishment in old animals improves hippocampal-dependent learning and memory in the water maze test.