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

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

Research output: Contribution to journalArticle

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 Rcan1KOmice.Wealso discovered thatRCAN1deletion or blockade ofRCAN1-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 Rcan1KOmice 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.

Original languageEnglish (US)
Pages (from-to)16930-16944
Number of pages15
JournalJournal of Neuroscience
Volume33
Issue number43
DOIs
StatePublished - 2013

Fingerprint

Calcineurin
Serotonin Uptake Inhibitors
Anxiety
Cyclic AMP Response Element-Binding Protein
Brain-Derived Neurotrophic Factor
Knockout Mice
Protein Phosphatase 1
Fluoxetine
Anti-Anxiety Agents
Brain
Therapeutic Uses
Calmodulin
Nuclear Proteins
Anxiety Disorders
Phosphorylation
Pharmacology
Calcium

ASJC Scopus subject areas

  • Neuroscience(all)

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Regulator of calcineurin 1 modulates expression of innate anxiety and anxiogenic responses to selective serotonin reuptake inhibitor treatment. / Hoeffer, Charles A.; Wong, Helen; Cain, Peter; Levenga, Josien; Cowansage, Kiriana K.; Choi, Yoon; Davy, Camille; Majmundar, Neil; Randy McMillan, D.; Rothermel, Beverly A.; Klann, Eric.

In: Journal of Neuroscience, Vol. 33, No. 43, 2013, p. 16930-16944.

Research output: Contribution to journalArticle

Hoeffer, CA, Wong, H, Cain, P, Levenga, J, Cowansage, KK, Choi, Y, Davy, C, Majmundar, N, Randy McMillan, D, Rothermel, BA & Klann, E 2013, 'Regulator of calcineurin 1 modulates expression of innate anxiety and anxiogenic responses to selective serotonin reuptake inhibitor treatment', Journal of Neuroscience, vol. 33, no. 43, pp. 16930-16944. https://doi.org/10.1523/JNEUROSCI.3513-12.2013
Hoeffer, Charles A. ; Wong, Helen ; Cain, Peter ; Levenga, Josien ; Cowansage, Kiriana K. ; Choi, Yoon ; Davy, Camille ; Majmundar, Neil ; Randy McMillan, D. ; Rothermel, Beverly A. ; Klann, Eric. / Regulator of calcineurin 1 modulates expression of innate anxiety and anxiogenic responses to selective serotonin reuptake inhibitor treatment. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 43. pp. 16930-16944.
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AU - Choi, Yoon

AU - Davy, Camille

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