title: Regulator of calcineurin 1 modulates expression of innate anxiety and anxiogenic responses to selective serotonin reuptake inhibitor treatment.
abstract: Regulator of calcineurin 1 (RCAN1) controls the activity of calcium/calmodulin-dependent phosphatase calcineurin (CaN), which has been implicated in human anxiety disorders. Previously, we reported that RCAN1 functioned as an inhibitor of CaN activity in the brain. However, we now find enhanced phosphorylation of a CaN substrate, cAMP response element-binding protein (CREB), in the brains of Rcan1 knock-out (KO) mice. Consistent with enhanced CREB activation, we also observe enhanced expression of a CREB transcriptional target, brain-derived neurotrophic factor (BDNF) in Rcan1 KO mice. We also discovered that RCAN1 deletion or blockade of RCAN1-CaN interaction reduced CaN and protein phosphatase-1 localization to nuclear-enriched protein fractions and promoted CREB activation. Because of the potential links between CREB, BDNF, and anxiety, we examined the role of RCAN1 in the expression of innate anxiety. Rcan1 KO mice displayed reduced anxiety in several tests of unconditioned anxiety. Acute pharmacological inhibition of CaN rescued these deficits while transgenic overexpression of human RCAN1 increased anxiety. Finally, we found that Rcan1 KO mice lacked the early anxiogenic response to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and had improved latency for its therapeutic anxiolytic effects. Together, our study suggests that RCAN1 plays an important role in the expression of anxiety-related and SSRI-related behaviors through CaN-dependent signaling pathways. These results identify RCAN1 as a mediator of innate emotional states and possible therapeutic target for anxiety.
authors.affiliation: Department of Neuroscience & Physiology, Druckenmiller Neuroscience Institute, New York University School of Medicine, Langone Medical Center, New York, New York 10016, Center for Neural Science, New York University, New York, New York 10003, Department of Psychology, Excelsior College, Albany, New York 12203, and Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Hoeffer
authors.forename: Helen
authors.initials: H
authors.lastname: Wong
authors.forename: Peter
authors.initials: P
authors.lastname: Cain
authors.forename: Josien
authors.initials: J
authors.lastname: Levenga
authors.forename: Kiriana K
authors.initials: KK
authors.lastname: Cowansage
authors.forename: Yoon
authors.initials: Y
authors.lastname: Choi
authors.forename: Camille
authors.initials: C
authors.lastname: Davy
authors.forename: Neil
authors.initials: N
authors.lastname: Majmundar
authors.forename: D Randy
authors.initials: DR
authors.lastname: McMillan
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
authors.forename: Eric
authors.initials: E
authors.lastname: Klann
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D002135:Calcium-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins; D005473:Fluoxetine / Q000627:therapeutic use*; D017353:Gene Deletion; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism; D011930:Reaction Time; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D019703:Calcineurin; D002135:Calcium-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D005473:Fluoxetine; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D054645:Protein Phosphatase 1; D017367:Selective Serotonin Reuptake Inhibitors; C492004:Creb1 protein, mouse; C511512:DSCR1 protein, mouse; C108612:RCAN1 protein, human