Forward genetics identifies a novel sleep mutant with sleep state inertia and REM sleep deficits

Gareth T. Banks, Mathilde C.C. Guillaumin, Ines Heise, Petrina Lau, Minghui Yin, Nora Bourbia, Carlos Aguilar, Michael R. Bowl, Chris Esapa, Laurence A. Brown, Sibah Hasan, Erica Tagliatti, Elizabeth Nicholson, Rasneer Sonia Bains, Sara Wells, Vladyslav V. Vyazovskiy, Kirill Volynski, Stuart N. Peirson, Patrick M. Nolan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


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.

Original languageEnglish
Article numbereabb3567
JournalScience Advances
Issue number33
Publication statusPublished - Aug 2020

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