TY - JOUR
T1 - A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning
AU - Hafez, Alexander K.
AU - Zimmerman, Amber J.
AU - Papageorgiou, Grigorios
AU - Chandrasekaran, Jayapriya
AU - Amoah, Stephen K.
AU - Lin, Rixing
AU - Lozano, Evelyn
AU - Pierotti, Caroline
AU - Dell'Orco, Michela
AU - Hartley, Brigham J.
AU - Alural, Begüm
AU - Lalonde, Jasmin
AU - Esposito, John Matthew
AU - Berretta, Sabina
AU - Squassina, Alessio
AU - Chillotti, Caterina
AU - Voloudakis, Georgios
AU - Shao, Zhiping
AU - Fullard, John F.
AU - Brennand, Kristen J.
AU - Turecki, Gustavo
AU - Roussos, Panos
AU - Perlis, Roy H.
AU - Haggarty, Stephen J.
AU - Perrone-Bizzozero, Nora
AU - Brigman, Jonathan L.
AU - Mellios, Nikolaos
N1 - Funding Information:
This work was supported by the NIGMS P20 grant ( 1P20-GM121176 ; N.M., A.K.H., and S.K.A.), a Young Investigator Grant (FP00000839; N.M.) by the Brain & Behavior Research Foundation , and a high-priority, short-term R56 award from the NIMH (1R56-MH119150; N.M.). This work was partially supported by NIH grants 5R01-AA026583 , R01-MH101454 , R01-MH106056 , R33-MH087896 , R01-AG067025 , R01-AG065582 , R01-AG050986 , R01-MH110921 , U01-MH116442 , R01-MH125246 , R01-MH106056 , and R01-MH109897 . Further support was available by the Veterans Affairs Merit grant BX002395 (to P.R.), a BBRF Young Investigator Grant (K.J.B.), the MGH Research Scholars Program (S.J.H.), and the New York Stem Cell Foundation (K.J.B.). B.A. was supported by the Scientific and Technological Council of Turkey (2214/A) International Research Fellowship Program. We would like to thank Dr. Maree Webster and the SMRI brain bank for providing us with postmortem brain specimen. We would also like to thank Brian Rodriguez, Cole Bird, and Mate Fisher for technical assistance; Dr. Fernando Valenzuela for advice on the manuscript; and the UNM Clinical & Translational Science Center (CTSC) for allowing us access to ddPCR equipment. The authors gratefully acknowledge use of the Center of Biomedical Research Excellence (COBRE) data (P20-GM103472) and the Function Biomedical Informatics Research Network (FBIRN) data.
Funding Information:
This work was supported by the NIGMS P20 grant (1P20-GM121176; N.M. A.K.H. and S.K.A.), a Young Investigator Grant (FP00000839; N.M.) by the Brain & Behavior Research Foundation, and a high-priority, short-term R56 award from the NIMH (1R56-MH119150; N.M.). This work was partially supported by NIH grants 5R01-AA026583, R01-MH101454, R01-MH106056, R33-MH087896, R01-AG067025, R01-AG065582, R01-AG050986, R01-MH110921, U01-MH116442, R01-MH125246, R01-MH106056, and R01-MH109897. Further support was available by the Veterans Affairs Merit grant BX002395 (to P.R.), a BBRF Young Investigator Grant (K.J.B.), the MGH Research Scholars Program (S.J.H.), and the New York Stem Cell Foundation (K.J.B.). B.A. was supported by the Scientific and Technological Council of Turkey (2214/A) International Research Fellowship Program. We would like to thank Dr. Maree Webster and the SMRI brain bank for providing us with postmortem brain specimen. We would also like to thank Brian Rodriguez, Cole Bird, and Mate Fisher for technical assistance; Dr. Fernando Valenzuela for advice on the manuscript; and the UNM Clinical & Translational Science Center (CTSC) for allowing us access to ddPCR equipment. The authors gratefully acknowledge use of the Center of Biomedical Research Excellence (COBRE) data (P20-GM103472) and the Function Biomedical Informatics Research Network (FBIRN) data. N.M. conceived the hypothesis; designed, performed, and supervised experiments; analyzed data; and wrote the manuscript. J.L.B. and N.P.-B. designed and supervised experiments, analyzed data, and provided feedback on the hypothesis and manuscript. A.K.H. A.J.Z. and G.P. designed and performed experiments, analyzed data, provided feedback on the hypothesis, and helped in manuscript preparation. All other authors performed experiments and analyzed data. All authors reviewed the paper. 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.).
Publisher Copyright:
© 2021 The Authors
PY - 2022/1/18
Y1 - 2022/1/18
N2 - 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.
AB - 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.
KW - Homer1
KW - OFC
KW - bipolar disorder
KW - circHomer1
KW - circRNAs
KW - cognitive flexibility
KW - reversal learning
UR - http://www.scopus.com/inward/record.url?scp=85122939254&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2021.110282
DO - 10.1016/j.celrep.2021.110282
M3 - Article
C2 - 35045295
AN - SCOPUS:85122939254
SN - 2211-1247
VL - 38
JO - Cell Reports
JF - Cell Reports
IS - 3
M1 - 110282
ER -