Coronin 1 Regulates Cognition and Behavior through Modulation of cAMP/Protein Kinase A Signaling

Rajesh Jayachandran,Jacques Schneider,Frédéric Gambino,Daniel Frey,Christian Müller,Christel Genoud,Yann Humeau,Catherine Fossoud,Rolf Jaussi,Somdeb Bosedasgupta,Malik Khelfaoui,Deborah Bartholdi,Andreas Lüthi,Richard A Kammerer,Philipp Müller,Chun-Lei Zhang,Jean Pieters,Vera Studer,Despina Moshous,Xiaolong Liu,Xander Houbaert,Xavier Deupí ,Hélène Rossez ,Michael Stieß ,Jean‐Pierre De Villartay

doi:10.1371/journal.pbio.1001820

Abstract

Author SummaryMemory and behavior depend on the proper transduction of signals in the brain, but the underlying molecular mechanisms remain largely unknown. Coronin 1 is a member of a highly conserved family of proteins, and although its gene lies in a chromosome region associated with neurobehavioral dysfunction in mice and men, it has never been directly ascribed a specific function in the brain. Here we show that coronin 1 plays an important role in cognition and behavior by regulating the cyclic AMP (cAMP) signaling pathway. We find that when cell surface receptors are activated, coronin 1 stimulates cAMP production and activation of protein kinase A. Coronin 1 deficiency resulted in severe functional defects at excitatory synapses. Furthermore, in both mice and humans, deletion or mutation of coronin 1 causes severe neurobehavioral defects, including social deficits, increased aggression, and learning disabilities. Strikingly, treatment with a membrane-permeable analogue of cAMP restored synaptic plasticity and behavioral defects in mice lacking coronin 1. Together this work not only shows a critical role for coronin 1 in neurobehavior but also defines a role for the coronin family in regulating the transmission of signals within cells.

Highlights

Behavioral and cognitive deficits comprise a heterogeneous collection of pathologies
Coronin 1 is a member of a highly conserved family of proteins, and its gene lies in a chromosome region associated with neurobehavioral dysfunction in mice and men, it has never been directly ascribed a specific function in the brain
We show that coronin 1 plays an important role in cognition and behavior by regulating the cyclic AMP signaling pathway

Summary

Introduction

Behavioral and cognitive deficits comprise a heterogeneous collection of pathologies. The molecular functions of the candidate genes that are associated with cognitive and behavioral impairment are beginning to be elucidated [1]; several of these molecules were shown to be located at synapses, suggesting that synaptic dysfunction is involved in neurobehavioral disorders [3,4,5,6]. For many of the candidate genes a direct link with neurobehavioral disorders as well an understanding of their molecular function remains unknown [7,8]. An important neuronal signaling cascade involved in synaptic plasticity and learning occurs downstream of G protein–coupled receptors, resulting in the activation of adenylate cyclase that produces cAMP through stimulation with the Gas subunit of trimeric G proteins [9,10,11,12]. An important neuronal signaling cascade involved in synaptic plasticity and learning occurs downstream of G protein–coupled receptors, resulting in the activation of adenylate cyclase that produces cAMP through stimulation with the Gas subunit of trimeric G proteins [9,10,11,12]. cAMP in turn activates protein kinase A (PKA), which drives long-term changes in synaptic efficacy

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