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

Uygun, D. S.; Yang, C.; Tilli, E. R.; Katsuki, F.; McKenna, J. T.; McNally, J. M.; Brown, R. E.; Basheer, R.

2020-12-15 neuroscience
10.1101/2020.12.15.422912 bioRxiv
Show abstract

Identification of mechanisms which increase deep sleep could lead to novel treatments which promote the restorative effects of sleep. Here, knockdown of the 3 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 3 subunits. Our results identify a functional role for GABAA receptors on Thalamic Reticular Nucleus neurons and suggest antagonism of 3 subunits as a strategy to enhance deep sleep. One Sentence SummarySelective genetic knockdown of the major subunit of GABAA receptors present in the thalamic reticular nucleus enhanced deep sleep in mice.

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