CRISPR knockdown of GABAA alpha3 subunits on thalamic reticular neurons enhances deep sleep

Identification of mechanisms which increase deep sleep could lead to novel treatments which promote the restorative effects of sleep. Here, knockdown of the α3 GABAA-receptor subunit from parvalbumin neurons in the thalamic reticular nucleus using CRISPR-Cas9 gene editing increased the thalamocortical delta oscillations implicated in many health-promoting effects of sleep. Inhibitory synaptic currents were strongly reduced in vitro . Effects were most pronounced in the mouse sleep (light) period. Further analysis identified a novel deep-sleep state in mice prior to NREM-REM transitions which was preferentially affected by deletion of α3 subunits. Our results identify a functional role for GABAA receptors on Thalamic Reticular Nucleus neurons and suggest antagonism of α3 subunits as a strategy to enhance deep sleep. One Sentence Summary Selective genetic knockdown of the major α subunit of GABAA receptors present in the thalamic reticular nucleus enhanced deep sleep in mice. ### Competing Interest Statement The authors have declared no competing interest.