SIRT6 deficiency causes neurotransmission defects in the mouse retina

DAFNE M SILBERMAN; K ROSS; PABLO SANDE; S KUBOTA; RS APTE; S RAMASWAMY; RAUL MOSTOSLAVSKY

Chicago

Congreso; 2015 SFN Annual Meeting; 2015

Society for Neuroscience

The retina is one of the major energy consuming tissues within the body and its energetic source for normal functioningcomes mainly from glucose metabolism. This necessity for glucose is evidenced by alteration in electroretinogram(ERG) responses and altered neurotransmitter release as described in ischemic and hypoglycemic conditions. Uponactivation of photoreceptors, G-coupled glutamate receptors (mGluR) regulate transmitter release by ON bipolar cellsultimately converting visual stimulation to patterns of activity of retinal ganglion cells (RGCs) leading to visual perceptionin the visual cortex. The synaptic transmission is a highly energy demanding event and it has been shown that a declinein energy supply and a disruption in bioenergy homeostasis play a critical role in multiple neuropathological conditions.It is therefore of physiological significance to have synaptic activity coupled with glucose homeostasis.SIRT6, a chromatin‐bound enzyme member of a conserved family of NAD(+)-dependent deacylases, regulate variousmetabolic pathways and have emerged as an important sensor of energy status in mammals. SIRT6 has been shown toregulate glycolitic genes as the glucose transporter GLUT1 and has been described as a tumor suppressor factor andas a critical modulator of DNA repair.Given the importance of glucose availability for retina function, the critical role for SIRT6 in modulating glycolysis and thelack of information about this sirtuin in the retina, the goal of this study was to provide a functional characterization ofSIRT6 in this tissue. We found that SIRT6 is expressed in the nuclei of cells in all retinal layers and is highly active, asshown by the significant increased levels of acetylation of it substrates, H3K9 and H3K56, in the SIRT6-KO retinacompared to the WT. In SIRT6 deficient mice (strain 129/J), the structure of the retina remained unchanged and nosignificant differences in the thickness of the layers between WT and KO mice were observed. However, SIRT6 deficientretinas exhibited increased apoptosis in the inner layers determined by TUNEL, downregulation of the G0-coupled type 6metabotropic glutamate receptor (Grm6) gene and upregulation of the glucose transporter GLUT1, indicating that bothneurotransmission and glucose levels in the retina might be regulated by SIRT6. Functionally, ERG analysis showedthat both scotopic and photopic a- and b-wave amplitudes were severely altered for all the light intensities analyzed inthe retina of SIRT6-KO mice, indicating a unique role for SIRT6 as a modulator of retinal function.