Knockdown of GABAA alpha3 subunits on thalamic reticular neurons enhances deep sleep in mice

David S. Uygun, Chun Yang, Elena R. Tilli, Fumi Katsuki, Erik L. Hodges, James T. McKenna, James M. McNally, Ritchie E. Brown and Radhika Basheer ()
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David S. Uygun: VA Boston Healthcare System and Harvard Medical School, Dept. of Psychiatry
Chun Yang: VA Boston Healthcare System and Harvard Medical School, Dept. of Psychiatry
Elena R. Tilli: Stonehill College, Department of Psychology
Fumi Katsuki: VA Boston Healthcare System and Harvard Medical School, Dept. of Psychiatry
Erik L. Hodges: VA Boston Healthcare System and Harvard Medical School, Dept. of Psychiatry
James T. McKenna: VA Boston Healthcare System and Harvard Medical School, Dept. of Psychiatry
James M. McNally: VA Boston Healthcare System and Harvard Medical School, Dept. of Psychiatry
Ritchie E. Brown: VA Boston Healthcare System and Harvard Medical School, Dept. of Psychiatry
Radhika Basheer: VA Boston Healthcare System and Harvard Medical School, Dept. of Psychiatry

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract Identification of mechanisms which increase deep sleep could lead to novel treatments which promote the restorative effects of sleep. Here, we show that knockdown of the α3 GABAA-receptor subunit from parvalbumin neurons in the thalamic reticular nucleus using CRISPR-Cas9 gene editing increased the thalamocortical delta (1.5–4 Hz) oscillations which are implicated in many health-promoting effects of sleep. Inhibitory synaptic currents in thalamic reticular parvalbumin neurons were strongly reduced in vitro. Further analysis revealed that delta power in long NREM bouts prior to NREM-REM transitions was preferentially affected by deletion of α3 subunits. Our results identify a role for GABAA receptors on thalamic reticular nucleus neurons and suggest antagonism of α3 subunits as a strategy to enhance delta activity during sleep.

Date: 2022
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DOI: 10.1038/s41467-022-29852-x

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