A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning.
Homer1
OFC
bipolar disorder
circHomer1
circRNAs
cognitive flexibility
reversal learning
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
18 01 2022
18 01 2022
Historique:
received:
23
11
2020
revised:
28
06
2021
accepted:
28
12
2021
entrez:
19
1
2022
pubmed:
20
1
2022
medline:
15
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35045295
pii: S2211-1247(21)01797-6
doi: 10.1016/j.celrep.2021.110282
pmc: PMC8809079
mid: NIHMS1772785
pii:
doi:
Substances chimiques
Homer Scaffolding Proteins
0
RNA, Circular
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
110282Subventions
Organisme : NIMH NIH HHS
ID : R01 MH125899
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH116442
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH101454
Pays : United States
Organisme : BLRD VA
ID : I01 BX002395
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH110921
Pays : United States
Organisme : NIMH NIH HHS
ID : R33 MH087896
Pays : United States
Organisme : NIMH NIH HHS
ID : F31 MH122121
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM121176
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG067025
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA026583
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG065582
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH125246
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH109897
Pays : United States
Organisme : NIMH NIH HHS
ID : R56 MH119150
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA025652
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG050986
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH106056
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests A.K.H. and N.M. have a financial interest as co-founders of Circular Genomics Inc. and are inventors of patents related to the use of circRNAs for brain disease diagnostics (N.M.) or therapeutics (N.M. and A.K.H.).
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