MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity

Orna Issler; Sharon Haramati; Evan D. Paul; Hiroshi Maeno; Inbal Navon; Rayya Zwang; Shosh Gil; Helen S. Mayberg; Boadie W. Dunlop; Andreas Menke; Rajeshwar Awatramani; Elisabeth B. Binder; Evan S. Deneris; Christopher A. Lowry; Alon Chen

doi:10.1016/j.neuron.2014.05.042

MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity

Orna Issler, Sharon Haramati, Evan D. Paul, Hiroshi Maeno, Inbal Navon, Rayya Zwang, Shosh Gil, Helen S. Mayberg, Boadie W. Dunlop, Andreas Menke, Rajeshwar Awatramani, Elisabeth B. Binder, Evan S. Deneris, Christopher A. Lowry, Alon Chen^*

^*Corresponding author for this work

Neurology

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

278 Scopus citations

Abstract

The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA "fingerprint" of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies.

Original language	English (US)
Pages (from-to)	344-360
Number of pages	17
Journal	Neuron
Volume	83
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2014.05.042
State	Published - Jul 16 2014

Funding

A.C. is the head of the Max Planck Society - Weizmann Institute of Science Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics. We thank Mr. Sharon Ovadia for his devoted assistance with animal care; Dr. Eran Hornstein for fruitful discussions; Dr. Shirley Horn-Saban, Dr. David Pilzer, and Anna Weisman for the microarray experiments; and Dr. Ester Feldmesser and Dr. Shifra Ben-Dor for bioinformatics. This work is supported by: an FP7 Grant from the European Research Council (260463); a NARSAD Independent Investigator Grant (20360) from the Brain & Behavior Research Foundation; a Research Grant from the Israel Science Foundation (803/11); a Research support from Roberto and Renata Ruhman; Nella and Leon Benoziyo Center for Neurological Diseases; the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Perlman Family Foundation, Founded by Louis L. and Anita M. Perlman; the Adelis Foundation; the Marc Besen and the Pratt Foundation; the Irving I. Moskowitz Foundation; Award Number R01MH086539 from the National Institute of Mental Health, and NIH grants RO1 MH062723 and P50 MH078028.

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2014.05.042

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Issler, O., Haramati, S., Paul, E. D., Maeno, H., Navon, I., Zwang, R., Gil, S., Mayberg, H. S., Dunlop, B. W., Menke, A., Awatramani, R., Binder, E. B., Deneris, E. S., Lowry, C. A., & Chen, A. (2014). MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity. Neuron, 83(2), 344-360. https://doi.org/10.1016/j.neuron.2014.05.042

@article{02189379606f4526bc5e550b0090516d,

title = "MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity",

abstract = "The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA {"}fingerprint{"} of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies.",

author = "Orna Issler and Sharon Haramati and Paul, {Evan D.} and Hiroshi Maeno and Inbal Navon and Rayya Zwang and Shosh Gil and Mayberg, {Helen S.} and Dunlop, {Boadie W.} and Andreas Menke and Rajeshwar Awatramani and Binder, {Elisabeth B.} and Deneris, {Evan S.} and Lowry, {Christopher A.} and Alon Chen",

note = "Funding Information: A.C. is the head of the Max Planck Society - Weizmann Institute of Science Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics. We thank Mr. Sharon Ovadia for his devoted assistance with animal care; Dr. Eran Hornstein for fruitful discussions; Dr. Shirley Horn-Saban, Dr. David Pilzer, and Anna Weisman for the microarray experiments; and Dr. Ester Feldmesser and Dr. Shifra Ben-Dor for bioinformatics. This work is supported by: an FP7 Grant from the European Research Council (260463); a NARSAD Independent Investigator Grant (20360) from the Brain & Behavior Research Foundation; a Research Grant from the Israel Science Foundation (803/11); a Research support from Roberto and Renata Ruhman; Nella and Leon Benoziyo Center for Neurological Diseases; the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Perlman Family Foundation, Founded by Louis L. and Anita M. Perlman; the Adelis Foundation; the Marc Besen and the Pratt Foundation; the Irving I. Moskowitz Foundation; Award Number R01MH086539 from the National Institute of Mental Health, and NIH grants RO1 MH062723 and P50 MH078028. ",

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Issler, O, Haramati, S, Paul, ED, Maeno, H, Navon, I, Zwang, R, Gil, S, Mayberg, HS, Dunlop, BW, Menke, A, Awatramani, R, Binder, EB, Deneris, ES, Lowry, CA & Chen, A 2014, 'MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity', Neuron, vol. 83, no. 2, pp. 344-360. https://doi.org/10.1016/j.neuron.2014.05.042

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T1 - MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity

AU - Issler, Orna

AU - Haramati, Sharon

AU - Paul, Evan D.

AU - Maeno, Hiroshi

AU - Navon, Inbal

AU - Zwang, Rayya

AU - Gil, Shosh

AU - Mayberg, Helen S.

AU - Dunlop, Boadie W.

AU - Menke, Andreas

AU - Awatramani, Rajeshwar

AU - Binder, Elisabeth B.

AU - Deneris, Evan S.

AU - Lowry, Christopher A.

AU - Chen, Alon

N1 - Funding Information: A.C. is the head of the Max Planck Society - Weizmann Institute of Science Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics. We thank Mr. Sharon Ovadia for his devoted assistance with animal care; Dr. Eran Hornstein for fruitful discussions; Dr. Shirley Horn-Saban, Dr. David Pilzer, and Anna Weisman for the microarray experiments; and Dr. Ester Feldmesser and Dr. Shifra Ben-Dor for bioinformatics. This work is supported by: an FP7 Grant from the European Research Council (260463); a NARSAD Independent Investigator Grant (20360) from the Brain & Behavior Research Foundation; a Research Grant from the Israel Science Foundation (803/11); a Research support from Roberto and Renata Ruhman; Nella and Leon Benoziyo Center for Neurological Diseases; the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; the Perlman Family Foundation, Founded by Louis L. and Anita M. Perlman; the Adelis Foundation; the Marc Besen and the Pratt Foundation; the Irving I. Moskowitz Foundation; Award Number R01MH086539 from the National Institute of Mental Health, and NIH grants RO1 MH062723 and P50 MH078028.

PY - 2014/7/16

Y1 - 2014/7/16

N2 - The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA "fingerprint" of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies.

AB - The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA "fingerprint" of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies.

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MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity

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