SIRT1 regulates dendritic development in hippocampal neurons.

Abstract

Dendritic arborization is required for proper neuronal connectivity. SIRT1, a NAD+ dependent histone deacetylase, has been associated to ageing and longevity, which in neurons is linked to neuronal differentiation and neuroprotection. In the present study, the role of SIRT1 in dendritic development was evaluated in cultured hippocampal neurons which were transfected at 3 days in vitro with a construct coding for SIRT1 or for the dominant negative SIRT1H363Y, which lacks the catalytic activity. Neurons overexpressing SIRT1 showed an increased dendritic arborization, while neurons overexpressing SIRT1H363Y showed a reduction in dendritic arbor complexity. The effect of SIRT1 was mimicked by treatment with resveratrol, a well known activator of SIRT1, which has no effect in neurons overexpressing SIRT1H363Y indicating that the effect of resveratrol was specifically mediated by SIRT1. Moreover, hippocampal neurons overexpressing SIRT1 were resistant to dendritic dystrophy induced by Aβ aggregates, an effect that was dependent on the deacetylase activity of SIRT1. Our findings indicate that SIRT1 plays a role in the development and maintenance of dendritic branching in hippocampal neurons, and suggest that these effects are mediated by the ROCK signaling pathway.