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

Alexander K. Hafez; Amber J. Zimmerman; Grigorios Papageorgiou; Jayapriya Chandrasekaran; Stephen K. Amoah; Rixing Lin; Evelyn Lozano; Caroline Pierotti; Michela Dell'Orco; Brigham J. Hartley; Begüm Alural; Jasmin Lalonde; John Matthew Esposito; Sabina Berretta; Alessio Squassina; Caterina Chillotti; Georgios Voloudakis; Zhiping Shao; John F. Fullard; Kristen J. Brennand; Gustavo Turecki; Panos Roussos; Roy H. Perlis; Stephen J. Haggarty; Nora Perrone-Bizzozero; Jonathan L. Brigman; Nikolaos Mellios

doi:10.1016/j.celrep.2021.110282

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

Alexander K. Hafez, Amber J. Zimmerman, Grigorios Papageorgiou, Jayapriya Chandrasekaran, Stephen K. Amoah, Rixing Lin, Evelyn Lozano, Caroline Pierotti, Michela Dell'Orco, Brigham J. Hartley, Begüm Alural, Jasmin Lalonde, John Matthew Esposito, Sabina Berretta, Alessio Squassina, Caterina Chillotti, Georgios Voloudakis, Zhiping Shao, John F. Fullard, Kristen J. BrennandGustavo Turecki, Panos Roussos, Roy H. Perlis, Stephen J. Haggarty, Nora Perrone-Bizzozero, Jonathan L. Brigman, Nikolaos Mellios

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

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.

Original language	English
Article number	110282
Journal	Cell Reports
Volume	38
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2021.110282
State	Published - 18 Jan 2022

Keywords

Homer1
OFC
bipolar disorder
circHomer1
circRNAs
cognitive flexibility
reversal learning

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10.1016/j.celrep.2021.110282

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Hafez, A. K., Zimmerman, A. J., Papageorgiou, G., Chandrasekaran, J., Amoah, S. K., Lin, R., Lozano, E., Pierotti, C., Dell'Orco, M., Hartley, B. J., Alural, B., Lalonde, J., Esposito, J. M., Berretta, S., Squassina, A., Chillotti, C., Voloudakis, G., Shao, Z., Fullard, J. F., ... Mellios, N. (2022). A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning. Cell Reports, 38(3), Article 110282. https://doi.org/10.1016/j.celrep.2021.110282

@article{127fa4a028884510b321da335dd5133c,

title = "A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning",

abstract = "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.",

keywords = "Homer1, OFC, bipolar disorder, circHomer1, circRNAs, cognitive flexibility, reversal learning",

author = "Hafez, {Alexander K.} and Zimmerman, {Amber J.} and Grigorios Papageorgiou and Jayapriya Chandrasekaran and Amoah, {Stephen K.} and Rixing Lin and Evelyn Lozano and Caroline Pierotti and Michela Dell'Orco and Hartley, {Brigham J.} and Beg{\"u}m Alural and Jasmin Lalonde and Esposito, {John Matthew} and Sabina Berretta and Alessio Squassina and Caterina Chillotti and Georgios Voloudakis and Zhiping Shao and Fullard, {John F.} and Brennand, {Kristen J.} and Gustavo Turecki and Panos Roussos and Perlis, {Roy H.} and Haggarty, {Stephen J.} and Nora Perrone-Bizzozero and Brigman, {Jonathan L.} and Nikolaos Mellios",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2022",

month = jan,

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doi = "10.1016/j.celrep.2021.110282",

language = "English",

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Hafez, AK, Zimmerman, AJ, Papageorgiou, G, Chandrasekaran, J, Amoah, SK, Lin, R, Lozano, E, Pierotti, C, Dell'Orco, M, Hartley, BJ, Alural, B, Lalonde, J, Esposito, JM, Berretta, S, Squassina, A, Chillotti, C, Voloudakis, G, Shao, Z, Fullard, JF, Brennand, KJ, Turecki, G, Roussos, P, Perlis, RH, Haggarty, SJ, Perrone-Bizzozero, N, Brigman, JL & Mellios, N 2022, 'A bidirectional competitive interaction between circHomer1 and Homer1b within the orbitofrontal cortex regulates reversal learning', Cell Reports, vol. 38, no. 3, 110282. https://doi.org/10.1016/j.celrep.2021.110282

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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

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

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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 -

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

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