Regulator of calcineurin 1 modulates expression of innate anxiety and anxiogenic responses to selective serotonin reuptake inhibitor treatment

Authors

Charles A. Hoeffer, 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.
Helen Wong
Peter Cain
Josien Levenga
Kiriana K. Cowansage
Yoon Choi
Camille Davy
Neil Majmundar
D Randy McMillan
Beverly A. Rothermel
Eric Klann

Document Type

Article

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.

Medical Subject Headings

Animals; Anxiety (drug therapy, metabolism); Brain (metabolism); Brain-Derived Neurotrophic Factor (genetics, metabolism); Calcineurin (metabolism); Calcium-Binding Proteins; Cyclic AMP Response Element-Binding Protein (metabolism); DNA-Binding Proteins; Fluoxetine (therapeutic use); Gene Deletion; Humans; Intracellular Signaling Peptides and Proteins (genetics, metabolism); Mice; Muscle Proteins (genetics, metabolism); Phosphorylation; Protein Phosphatase 1 (metabolism); Reaction Time; Selective Serotonin Reuptake Inhibitors (therapeutic use)

Publication Date

10-23-2013

Publication Title

The Journal of neuroscience : the official journal of the Society for Neuroscience

E-ISSN

1529-2401

Volume

33

Issue

43

First Page

16930

Last Page

44

PubMed ID

24155299

Digital Object Identifier (DOI)

10.1523/JNEUROSCI.3513-12.2013

Recommended Citation

Hoeffer, Charles A.; Wong, Helen; Cain, Peter; Levenga, Josien; Cowansage, Kiriana K.; Choi, Yoon; Davy, Camille; Majmundar, Neil; McMillan, D Randy; Rothermel, Beverly A.; and Klann, Eric, "Regulator of calcineurin 1 modulates expression of innate anxiety and anxiogenic responses to selective serotonin reuptake inhibitor treatment" (2013). Neurosurgery. 2223.
https://scholar.barrowneuro.org/neurosurgery/2223