A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning

被引：31

作者：

Hafez, Alexander K. ^{[1
,2
]}

Zimmerman, Amber J. ^{[1
]}

Papageorgiou, Grigorios ^{[1
]}

Chandrasekaran, Jayapriya ^{[1
]}

Amoah, Stephen K. ^{[1
,2
,19
,22
]}

Lin, Rixing ^{[3
]}

Lozano, Evelyn ^{[1
]}

Pierotti, Caroline ^{[1
]}

Dell'Orco, Michela ^{[1
]}

Hartley, Brigham J. ^{[4
,5
,23
,24
]}

Alural, Begum ^{[6
,7
,8
]}

Lalonde, Jasmin ^{[6
,7
,8
,21
,25
]}

Esposito, John Matthew ^{[9
]}

Berretta, Sabina ^{[9
,10
,11
]}

Squassina, Alessio ^{[12
]}

Chillotti, Caterina ^{[13
]}

Voloudakis, Georgios ^{[14
,15
,16
]}

Shao, Zhipin ^{[14
,15
,16
]}

Fullard, John F. ^{[14
,15
,16
]}

Brennand, Kristen J. ^{[4
,5
,15
,23
,24
]}

Turecki, Gustavo ^{[3
]}

Roussos, Panos ^{[14
,15
,16
,17
,18
,19
]}

Perlis, Roy H. ^{[10
,20
,21
]}

Haggarty, Stephen J. ^{[6
,7
,8
]}

Perrone-Bizzozero, Nora ^{[1
]}

Brigman, Jonathan L. ^{[1
]}

Mellios, Nikolaos ^{[1
,2
]}

机构：

[1] Univ New Mexico, Sch Med, Dept Neurosci, Albuquerque, NM 87131 USA

[2] Univ New Mexico, Hlth Sci Ctr, Autophagy Inflammat & Metab Ctr Biomed Res Excell, Albuquerque, NM 87131 USA

[3] McGill Univ, Douglas Mental Hlth Univ Inst, Dept Psychiat, McGill Grp Suicide Studies, Montreal, PQ, Canada

[4] Icahn Sch Med Mt Sinai, Pamela Sklar Div Psychiat Genom, Friedman Brain Inst, Dept Genet, New York, NY 10029 USA

[5] Icahn Sch Med Mt Sinai, Pamela Sklar Div Psychiat Genom, Friedman Brain Inst, Dept Genom Sci,Neurosci & Psychiat, New York, NY 10029 USA

[6] Massachusetts Gen Hosp, Dept Neurol, Ctr Genom Med, Chem Neurobiol Lab, Boston, MA 02114 USA

[7] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA

[8] Harvard Med Sch, Boston, MA 02115 USA

[9] McLean Hosp, Translat Neurosci Lab, 115 Mill St, Belmont, MA 02178 USA

[10] Harvard Med Sch, Dept Psychiat, Boston, MA 02115 USA

[11] Harvard Med Sch, Program Neurosci, Boston, MA 02115 USA

[12] Univ Cagliari, Sect Neurosci & Clin Pharmacol, Dept Biomed Sci, Cagliari, Italy

[13] Univ Hosp Agcy Cagliari, Unit Clin Pharmacol, Cagliari, Italy

[14] Dept Genet & Genom Sci, New York, NY USA

[15] Icahn Inst Data Sci & Genom Technol, New York, NY USA

[16] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[17] James J Peters VA Med Ctr, Mental Illness Res Ctr, Bronx, NY USA

[18] James J Peters VA Med Ctr, Mental Illness Educ Ctr, Bronx, NY USA

[19] James J Peters VA Med Ctr, Mental Illness Clin Ctr, Bronx, NY USA

[20] Harvard Med Sch, Dept Psychiat, Boston, MA USA

[21] Massachusetts Gen Hosp, Ctr Expt Drugs & Diagnost, Ctr Genom Med, Boston, MA 02114 USA

[22] Univ Cape Coast, Cape Coast, Ghana

[23] Yale Univ, Sch Med, Dept Psychiat, Div Mol Psychiat, New Haven, CT USA

[24] Yale Univ, Sch Med, Dept Genet, Div Mol Psychiat, New Haven, CT USA

[25] Univ Guelph, Dept Mol & Cellular Biol, Guelph, ON, Canada

来源：

CELL REPORTS | 2022年 / 38卷 / 03期

关键词：

EXON-JUNCTION COMPLEX; CIRCULAR RNAS; DOWN-REGULATION; BIPOLAR DISORDER; EXPRESSION; PROTEINS; MICRORNA; SCHIZOPHRENIA; FLEXIBILITY; PROTECTS;

D O I：

10.1016/j.celrep.2021.110282

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Although circular RNAs (circRNAs) are enriched in the brain, their relevance for brain function and psychiatric disorders is poorly understood. Here, we show that circHomer1 is inversely associated with relative HOMER1B mRNA isoform levels in both the orbitofrontal cortex (OFC) and stem-cell-derived neuronal cultures of subjects with psychiatric disorders. We further demonstrate that in vivo circHomer1 knockdown (KD) within the OFC can inhibit the synaptic expression of Homer1b mRNA. Furthermore, we show that circHomer1 directly binds to Homer1b mRNA and that Homer1b-specific KD increases synaptic circHomer1 levels and improves OFC-mediated behavioral flexibility. Importantly, double circHomer1 and Homer1b in vivo co-KD results in a complete rescue in circHomer1-associated alterations in both chance reversal learning and synaptic gene expression. Lastly, we uncover an RNA-binding protein that can directly bind to circHomer1 and promote its biogenesis. Taken together. our data provide mechanistic insights into the importance of circRNAs in brain function and disease.

引用

页数：23

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