The CHD8/CHD7/Kismet family links blood-brain barrier glia and serotonin to ASD-associated sleep defects

被引：19

作者：

Coll-Tane, Mireia ^{[1
]}

Gong, Naihua N. ^{[2
,3
]}

Belfer, Samuel J. ^{[2
,3
]}

van Renssen, Lara, V ^{[1
]}

Kurtz-Nelson, Evangeline C. ^{[4
]}

Szuperak, Milan ^{[2
,3
]}

Eidhof, Ilse ^{[1
]}

van Reijmersdal, Boyd ^{[1
]}

Terwindt, Isabel ^{[1
]}

Durkin, Jaclyn ^{[2
,3
]}

Verheij, Michel M. M. ^{[5
]}

Kiln, Chang N. ^{[6
,7
]}

Hudac, Caitlin M. ^{[8
,9
]}

Nowakowski, Tomasz J. ^{[6
,7
]}

Bernier, Raphael A. ^{[4
]}

Pillen, Sigrid ^{[10
]}

Earl, Rachel K. ^{[4
]}

Eichler, Evan E. ^{[11
,12
]}

Kleefstra, Tjitske ^{[1
]}

Kayser, Matthew S. ^{[2
,3
]}

Schenck, Annette ^{[1
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Human Genet, NL-6525 GA Nijmegen, Netherlands

[2] Univ Penn, Perelman Sch Med, Dept Psychiat, Chronobiol & Sleep Inst, Philadelphia, PA 19104 USA

[3] Univ Penn, Perelman Sch Med, Dept Behav Sci, Chronobiol & Sleep Inst, Philadelphia, PA 19104 USA

[4] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98185 USA

[5] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci,Ctr Neurosci, Nijmegen, Netherlands

[6] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA

[7] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA

[8] Univ Alabama, Ctr Youth Dev & Intervent, Tuscaloosa, AL 35487 USA

[9] Univ Alabama, Dept Psychol, Box 870348, Tuscaloosa, AL 35487 USA

[10] Kempenhaeghe, Ctr Sleep Med, Heeze, Netherlands

[11] Univ Washington, Dept Genome Sci, Sch Med, Seattle, WA 98195 USA

[12] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA

来源：

SCIENCE ADVANCES | 2021年 / 7卷 / 23期

基金：

英国医学研究理事会;

关键词：

AUTISM SPECTRUM DISORDER; CONSENSUS STATEMENT; RECOMMENDED AMOUNT; CIRCADIAN-RHYTHMS; AMERICAN ACADEMY; DROSOPHILA MODEL; CNS MYELINATION; RISK GENES; CHD8; EXPRESSION;

D O I：

10.1126/sciadv.abe2626

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Sleep disturbances in autism and neurodevelopmental disorders are common and adversely affect patient's quality of life, yet the underlying mechanisms are understudied. We found that individuals with mutations in CHD8, among the highest-confidence autism risk genes, or CHD7 suffer from disturbed sleep maintenance. These defects are recapitulated in Drosophila mutants affecting kismet, the sole CHD8/CHD7 ortholog. We show that Kismet is required in glia for early developmental and adult sleep architecture. This role localizes to subperineurial glia constituting the blood-brain barrier. We demonstrate that Kismet-related sleep disturbances are caused by high serotonin during development, paralleling a well-established but genetically unsolved autism endophenotype. Despite their developmental origin, Kismet's sleep architecture defects can be reversed in adulthood by a behavioral regime resembling human sleep restriction therapy. Our findings provide fundamental insights into glial regulation of sleep and propose a causal mechanistic link between the CHD8/CHD7/Kismet family, developmental hyperserotonemia, and autism-associated sleep disturbances.

引用

页数：16