Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology

Andreia Gomes-Duarte; Morten T. Venø; Marina de Wit; Ketharini Senthilkumar; Mark H. Broekhoven; Joëlle van den Herik; Fleur R. Heeres; Daniëlle van Rossum; Mateja Rybiczka-Tesulov; Ivano Legnini; Peter C. van Rijen; Pieter van Eijsden; Peter H. Gosselaar; Nikolaus Rajewsky; Jørgen Kjems; Vamshidhar R. Vangoor; R. Jeroen Pasterkamp

doi:10.3389/fnmol.2022.832133

Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology

Andreia Gomes-Duarte, Morten T. Venø, Marina de Wit, Ketharini Senthilkumar, Mark H. Broekhoven, Joëlle van den Herik, Fleur R. Heeres, Daniëlle van Rossum, Mateja Rybiczka-Tesulov, Ivano Legnini, Peter C. van Rijen, Pieter van Eijsden, Peter H. Gosselaar, Nikolaus Rajewsky, Jørgen Kjems, Vamshidhar R. Vangoor, R. Jeroen Pasterkamp^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

8 Citations (Scopus)

Abstract

Mesial temporal lobe epilepsy (mTLE) is a chronic disease characterized by recurrent seizures that originate in the temporal lobes of the brain. Anti-epileptic drugs (AEDs) are the standard treatment for managing seizures in mTLE patients, but are frequently ineffective. Resective surgery is an option for some patients, but does not guarantee a postoperative seizure-free period. Therefore, further insight is needed into the pathogenesis of mTLE to enable the design of new therapeutic strategies. Circular RNAs (circRNAs) have been identified as important regulators of neuronal function and have been implicated in epilepsy. However, the mechanisms through which circRNAs contribute to epileptogenesis remain unknown. Here, we determine the circRNA transcriptome of the hippocampus and cortex of mTLE patients by using RNA-seq. We report 333 differentially expressed (DE) circRNAs between healthy individuals and mTLE patients, of which 23 circRNAs displayed significant adjusted p-values following multiple testing correction. Interestingly, hippocampal expression of circ_Satb1, a circRNA derived from special AT-rich sequence binding protein 1 (SATB1), is decreased in both mTLE patients and in experimental epilepsy. Our work shows that circ_Satb1 displays dynamic patterns of neuronal expression in vitro and in vivo. Further, circ_Satb1-specific knockdown using CRISPR/CasRx approaches in hippocampal cultures leads to defects in dendritic spine morphology, a cellular hallmark of mTLE. Overall, our results identify a novel epilepsy-associated circRNA with disease-specific expression and previously unidentified cellular effects that are relevant for epileptogenesis.

Original language	English
Article number	832133
Journal	Frontiers in Molecular Neuroscience
Volume	15
ISSN	1662-5099
DOIs	https://doi.org/10.3389/fnmol.2022.832133
Publication status	Published - Mar 2022

Keywords

circular RNA
dendritic spine
epilepsy
hippocampus
RNA-sequencing

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Gomes-Duarte, A., Venø, M. T., de Wit, M., Senthilkumar, K., Broekhoven, M. H., van den Herik, J., Heeres, F. R., van Rossum, D., Rybiczka-Tesulov, M., Legnini, I., van Rijen, P. C., van Eijsden, P., Gosselaar, P. H., Rajewsky, N., Kjems, J., Vangoor, V. R., & Pasterkamp, R. J. (2022). Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology. Frontiers in Molecular Neuroscience, 15, Article 832133. https://doi.org/10.3389/fnmol.2022.832133

@article{d318d51c01c147fa884dec4cf8daafaa,

title = "Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology",

abstract = "Mesial temporal lobe epilepsy (mTLE) is a chronic disease characterized by recurrent seizures that originate in the temporal lobes of the brain. Anti-epileptic drugs (AEDs) are the standard treatment for managing seizures in mTLE patients, but are frequently ineffective. Resective surgery is an option for some patients, but does not guarantee a postoperative seizure-free period. Therefore, further insight is needed into the pathogenesis of mTLE to enable the design of new therapeutic strategies. Circular RNAs (circRNAs) have been identified as important regulators of neuronal function and have been implicated in epilepsy. However, the mechanisms through which circRNAs contribute to epileptogenesis remain unknown. Here, we determine the circRNA transcriptome of the hippocampus and cortex of mTLE patients by using RNA-seq. We report 333 differentially expressed (DE) circRNAs between healthy individuals and mTLE patients, of which 23 circRNAs displayed significant adjusted p-values following multiple testing correction. Interestingly, hippocampal expression of circ_Satb1, a circRNA derived from special AT-rich sequence binding protein 1 (SATB1), is decreased in both mTLE patients and in experimental epilepsy. Our work shows that circ_Satb1 displays dynamic patterns of neuronal expression in vitro and in vivo. Further, circ_Satb1-specific knockdown using CRISPR/CasRx approaches in hippocampal cultures leads to defects in dendritic spine morphology, a cellular hallmark of mTLE. Overall, our results identify a novel epilepsy-associated circRNA with disease-specific expression and previously unidentified cellular effects that are relevant for epileptogenesis.",

keywords = "circular RNA, dendritic spine, epilepsy, hippocampus, RNA-sequencing",

author = "Andreia Gomes-Duarte and Ven{\o}, {Morten T.} and {de Wit}, Marina and Ketharini Senthilkumar and Broekhoven, {Mark H.} and {van den Herik}, Jo{\"e}lle and Heeres, {Fleur R.} and {van Rossum}, Dani{\"e}lle and Mateja Rybiczka-Tesulov and Ivano Legnini and {van Rijen}, {Peter C.} and {van Eijsden}, Pieter and Gosselaar, {Peter H.} and Nikolaus Rajewsky and J{\o}rgen Kjems and Vangoor, {Vamshidhar R.} and Pasterkamp, {R. Jeroen}",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 Gomes-Duarte, Ven{\o}, de Wit, Senthilkumar, Broekhoven, van den Herik, Heeres, van Rossum, Rybiczka-Tesulov, Legnini, van Rijen, van Eijsden, Gosselaar, Rajewsky, Kjems, Vangoor and Pasterkamp.",

year = "2022",

month = mar,

doi = "10.3389/fnmol.2022.832133",

language = "English",

volume = "15",

journal = "Frontiers in Molecular Neuroscience",

issn = "1662-5099",

publisher = "Frontiers Media SA",

}

Gomes-Duarte, A, Venø, MT, de Wit, M, Senthilkumar, K, Broekhoven, MH, van den Herik, J, Heeres, FR, van Rossum, D, Rybiczka-Tesulov, M, Legnini, I, van Rijen, PC, van Eijsden, P, Gosselaar, PH, Rajewsky, N, Kjems, J, Vangoor, VR & Pasterkamp, RJ 2022, 'Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology', Frontiers in Molecular Neuroscience, vol. 15, 832133. https://doi.org/10.3389/fnmol.2022.832133

Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology. / Gomes-Duarte, Andreia; Venø, Morten T.; de Wit, Marina et al.
In: Frontiers in Molecular Neuroscience, Vol. 15, 832133, 03.2022.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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T1 - Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology

AU - Gomes-Duarte, Andreia

AU - Venø, Morten T.

AU - de Wit, Marina

AU - Senthilkumar, Ketharini

AU - Broekhoven, Mark H.

AU - van den Herik, Joëlle

AU - Heeres, Fleur R.

AU - van Rossum, Daniëlle

AU - Rybiczka-Tesulov, Mateja

AU - Legnini, Ivano

AU - van Rijen, Peter C.

AU - van Eijsden, Pieter

AU - Gosselaar, Peter H.

AU - Rajewsky, Nikolaus

AU - Kjems, Jørgen

AU - Vangoor, Vamshidhar R.

AU - Pasterkamp, R. Jeroen

N1 - Publisher Copyright: Copyright © 2022 Gomes-Duarte, Venø, de Wit, Senthilkumar, Broekhoven, van den Herik, Heeres, van Rossum, Rybiczka-Tesulov, Legnini, van Rijen, van Eijsden, Gosselaar, Rajewsky, Kjems, Vangoor and Pasterkamp.

PY - 2022/3

Y1 - 2022/3

N2 - Mesial temporal lobe epilepsy (mTLE) is a chronic disease characterized by recurrent seizures that originate in the temporal lobes of the brain. Anti-epileptic drugs (AEDs) are the standard treatment for managing seizures in mTLE patients, but are frequently ineffective. Resective surgery is an option for some patients, but does not guarantee a postoperative seizure-free period. Therefore, further insight is needed into the pathogenesis of mTLE to enable the design of new therapeutic strategies. Circular RNAs (circRNAs) have been identified as important regulators of neuronal function and have been implicated in epilepsy. However, the mechanisms through which circRNAs contribute to epileptogenesis remain unknown. Here, we determine the circRNA transcriptome of the hippocampus and cortex of mTLE patients by using RNA-seq. We report 333 differentially expressed (DE) circRNAs between healthy individuals and mTLE patients, of which 23 circRNAs displayed significant adjusted p-values following multiple testing correction. Interestingly, hippocampal expression of circ_Satb1, a circRNA derived from special AT-rich sequence binding protein 1 (SATB1), is decreased in both mTLE patients and in experimental epilepsy. Our work shows that circ_Satb1 displays dynamic patterns of neuronal expression in vitro and in vivo. Further, circ_Satb1-specific knockdown using CRISPR/CasRx approaches in hippocampal cultures leads to defects in dendritic spine morphology, a cellular hallmark of mTLE. Overall, our results identify a novel epilepsy-associated circRNA with disease-specific expression and previously unidentified cellular effects that are relevant for epileptogenesis.

AB - Mesial temporal lobe epilepsy (mTLE) is a chronic disease characterized by recurrent seizures that originate in the temporal lobes of the brain. Anti-epileptic drugs (AEDs) are the standard treatment for managing seizures in mTLE patients, but are frequently ineffective. Resective surgery is an option for some patients, but does not guarantee a postoperative seizure-free period. Therefore, further insight is needed into the pathogenesis of mTLE to enable the design of new therapeutic strategies. Circular RNAs (circRNAs) have been identified as important regulators of neuronal function and have been implicated in epilepsy. However, the mechanisms through which circRNAs contribute to epileptogenesis remain unknown. Here, we determine the circRNA transcriptome of the hippocampus and cortex of mTLE patients by using RNA-seq. We report 333 differentially expressed (DE) circRNAs between healthy individuals and mTLE patients, of which 23 circRNAs displayed significant adjusted p-values following multiple testing correction. Interestingly, hippocampal expression of circ_Satb1, a circRNA derived from special AT-rich sequence binding protein 1 (SATB1), is decreased in both mTLE patients and in experimental epilepsy. Our work shows that circ_Satb1 displays dynamic patterns of neuronal expression in vitro and in vivo. Further, circ_Satb1-specific knockdown using CRISPR/CasRx approaches in hippocampal cultures leads to defects in dendritic spine morphology, a cellular hallmark of mTLE. Overall, our results identify a novel epilepsy-associated circRNA with disease-specific expression and previously unidentified cellular effects that are relevant for epileptogenesis.

KW - circular RNA

KW - dendritic spine

KW - epilepsy

KW - hippocampus

KW - RNA-sequencing

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U2 - 10.3389/fnmol.2022.832133

DO - 10.3389/fnmol.2022.832133

M3 - Journal article

C2 - 35310884

AN - SCOPUS:85127185226

SN - 1662-5099

VL - 15

JO - Frontiers in Molecular Neuroscience

JF - Frontiers in Molecular Neuroscience

M1 - 832133

ER -

Expression of Circ_Satb1 Is Decreased in Mesial Temporal Lobe Epilepsy and Regulates Dendritic Spine Morphology

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Keywords

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