TY - JOUR
T1 - MicroRNA 135 is essential for chronic stress resiliency, antidepressant efficacy, and intact serotonergic activity
AU - Issler, Orna
AU - Haramati, Sharon
AU - Paul, ED
AU - Maeno, H
AU - Navon, Inbal
AU - Zwang, Raaya
AU - Gil, Simone
AU - Mayberg, HS
AU - Dunlop, BW
AU - Menke, A
AU - Awatramani, R
AU - Binder, EB
AU - Deneris, ES
AU - Lowry, CA
AU - Chen, Alon
N1 - European Research Council [260463]; NARSAD from the Brain & Behavior Research Foundation [20360]; Israel Science Foundation [803/11]; Nella and Leon Benoziyo Center for Neurological Diseases; Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; Perlman Family Foundation; Adelis Foundation; Marc Besen and the Pratt Foundation; Irving I. Moskowitz Foundation; National Institute of Mental Health [R01MH086539]; NIH [RO1 MH062723, P50 MH078028] 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.
UR - http://www.scopus.com/inward/record.url?scp=84904368019&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2014.05.042
DO - 10.1016/j.neuron.2014.05.042
M3 - مقالة
SN - 0896-6273
VL - 83
SP - 344
EP - 360
JO - Neuron
JF - Neuron
IS - 2
ER -