PMID- 24155299 OWN - NLM STAT- MEDLINE DCOM- 20131223 LR - 20221207 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 33 IP - 43 DP - 2013 Oct 23 TI - Regulator of calcineurin 1 modulates expression of innate anxiety and anxiogenic responses to selective serotonin reuptake inhibitor treatment. PG - 16930-44 LID - 10.1523/JNEUROSCI.3513-12.2013 [doi] AB - 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. FAU - Hoeffer, Charles A AU - Hoeffer CA AD - 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. FAU - Wong, Helen AU - Wong H FAU - Cain, Peter AU - Cain P FAU - Levenga, Josien AU - Levenga J FAU - Cowansage, Kiriana K AU - Cowansage KK FAU - Choi, Yoon AU - Choi Y FAU - Davy, Camille AU - Davy C FAU - Majmundar, Neil AU - Majmundar N FAU - McMillan, D Randy AU - McMillan DR FAU - Rothermel, Beverly A AU - Rothermel BA FAU - Klann, Eric AU - Klann E LA - eng GR - HL072016/HL/NHLBI NIH HHS/United States GR - HL097768/HL/NHLBI NIH HHS/United States GR - R01 NS034007/NS/NINDS NIH HHS/United States GR - R01 NS047384/NS/NINDS NIH HHS/United States GR - NS047384/NS/NINDS NIH HHS/United States GR - R37 NS034007/NS/NINDS NIH HHS/United States GR - R29 NS034007/NS/NINDS NIH HHS/United States GR - R01 HL072016/HL/NHLBI NIH HHS/United States GR - NS034007/NS/NINDS NIH HHS/United States GR - F31 NS083277/NS/NINDS NIH HHS/United States GR - R01 HL097768/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Calcium-Binding Proteins) RN - 0 (Creb1 protein, mouse) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (DNA-Binding Proteins) RN - 0 (DSCR1 protein, mouse) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Muscle Proteins) RN - 0 (RCAN1 protein, human) RN - 0 (Serotonin Uptake Inhibitors) RN - 01K63SUP8D (Fluoxetine) RN - EC 3.1.3.16 (Calcineurin) RN - EC 3.1.3.16 (Protein Phosphatase 1) SB - IM MH - Animals MH - Anxiety/drug therapy/*metabolism MH - Brain/metabolism MH - Brain-Derived Neurotrophic Factor/genetics/metabolism MH - Calcineurin/metabolism MH - Calcium-Binding Proteins MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - DNA-Binding Proteins MH - Fluoxetine/*therapeutic use MH - Gene Deletion MH - Humans MH - Intracellular Signaling Peptides and Proteins/genetics/*metabolism MH - Mice MH - Muscle Proteins/genetics/*metabolism MH - Phosphorylation MH - Protein Phosphatase 1/metabolism MH - Reaction Time MH - Selective Serotonin Reuptake Inhibitors/*therapeutic use PMC - PMC3807023 EDAT- 2013/10/25 06:00 MHDA- 2013/12/24 06:00 PMCR- 2014/04/23 CRDT- 2013/10/25 06:00 PHST- 2013/10/25 06:00 [entrez] PHST- 2013/10/25 06:00 [pubmed] PHST- 2013/12/24 06:00 [medline] PHST- 2014/04/23 00:00 [pmc-release] AID - 33/43/16930 [pii] AID - 3513-12 [pii] AID - 10.1523/JNEUROSCI.3513-12.2013 [doi] PST - ppublish SO - J Neurosci. 2013 Oct 23;33(43):16930-44. doi: 10.1523/JNEUROSCI.3513-12.2013.