@article{discovery10109189, number = {33}, year = {2020}, title = {Forward genetics identifies a novel sleep mutant with sleep state inertia and REM sleep deficits}, journal = {Science Advances}, volume = {6}, note = {This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/}, month = {August}, author = {Banks, GT and Guillaumin, MCC and Heise, I and Lau, P and Yin, M and Bourbia, N and Aguilar, C and Bowl, MR and Esapa, C and Brown, LA and Hasan, S and Tagliatti, E and Nicholson, E and Bains, RS and Wells, S and Vyazovskiy, VV and Volynski, K and Peirson, SN and Nolan, PM}, url = {https://doi.org/10.1126/sciadv.abb3567}, abstract = {Switches between global sleep and wakefulness states are believed to be dictated by top-down influences arising from subcortical nuclei. Using forward genetics and in vivo electrophysiology, we identified a recessive mouse mutant line characterized by a substantially reduced propensity to transition between wake and sleep states with an especially pronounced deficit in initiating rapid eye movement (REM) sleep episodes. The causative mutation, an Ile102Asn substitution in the synaptic vesicular protein, VAMP2, was associated with morphological synaptic changes and specific behavioral deficits, while in vitro electrophysiological investigations with fluorescence imaging revealed a markedly diminished probability of vesicular release in mutants. Our data show that global shifts in the synaptic efficiency across brain-wide networks leads to an altered probability of vigilance state transitions, possibly as a result of an altered excitability balance within local circuits controlling sleep-wake architecture.} }