title: Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling.
abstract: Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling. We found that coronin 1 is specifically expressed in excitatory but not inhibitory neurons and that coronin 1 deficiency results in loss of excitatory synapses and severe neurobehavioral disabilities, including reduced anxiety, social deficits, increased aggression, and learning defects. Electrophysiological analysis of excitatory synaptic transmission in amygdala revealed that coronin 1 was essential for cyclic-AMP-protein kinase A-dependent presynaptic plasticity. We further show that upon cell surface stimulation, coronin 1 interacted with the G protein subtype Gαs to stimulate the cAMP/PKA pathway. The absence of coronin 1 or expression of coronin 1 mutants unable to interact with Gαs resulted in a marked reduction in cAMP signaling. Strikingly, synaptic plasticity and behavioral defects of coronin 1-deficient mice were restored by in vivo infusion of a membrane-permeable cAMP analogue. Together these results identify coronin 1 as being important for cognition and behavior through its activity in promoting cAMP/PKA-dependent synaptic plasticity and may open novel avenues for the dissection of signal transduction pathways involved in neurobehavioral processes.
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Jayachandran
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Somdeb
authors.initials: S
authors.lastname: Bosedasgupta
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Philipp
authors.initials: P
authors.lastname: Müller
authors.affiliation: Interdisciplinary Institute for Neuroscience, Bordeaux, France.
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Zhang
authors.affiliation: Hospital Necker, Paris, France.
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Vera
authors.initials: V
authors.lastname: Studer
authors.affiliation: Department of Radiology, University Children Hospital, UKBB, Basel, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Schneider
authors.affiliation: Center for Cellular Imaging and NanoAnalytics, University of Basel, Basel, Switzerland; Friedrich Miescher Institute, Basel, Switzerland.
authors.forename: Christel
authors.initials: C
authors.lastname: Genoud
authors.affiliation: Centre Hospitalier Universitaire de Nice, Nice, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fossoud
authors.affiliation: Interdisciplinary Institute for Neuroscience, Bordeaux, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Gambino
authors.affiliation: Interdisciplinary Institute for Neuroscience, Bordeaux, France.
authors.forename: Malik
authors.initials: M
authors.lastname: Khelfaoui
authors.affiliation: Friedrich Miescher Institute, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.affiliation: University Hospital Basel, Basel, Switzerland.
authors.forename: Deborah
authors.initials: D
authors.lastname: Bartholdi
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Helene
authors.initials: H
authors.lastname: Rossez
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Stiess
authors.affiliation: Interdisciplinary Institute for Neuroscience, Bordeaux, France.
authors.forename: Xander
authors.initials: X
authors.lastname: Houbaert
authors.affiliation: Biomolecular Research Laboratory, Paul Scherrer Institute, Villigen, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Jaussi
authors.affiliation: Biomolecular Research Laboratory, Paul Scherrer Institute, Villigen, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Frey
authors.affiliation: Biomolecular Research Laboratory, Paul Scherrer Institute, Villigen, Switzerland.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kammerer
authors.affiliation: Biomolecular Research Laboratory, Paul Scherrer Institute, Villigen, Switzerland; Condensed Matter Theory, Paul Scherrer Institute, Villigen, Switzerland.
authors.forename: Xavier
authors.initials: X
authors.lastname: Deupi
authors.affiliation: Hospital Necker, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
authors.affiliation: Friedrich Miescher Institute, Basel, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lüthi
authors.affiliation: Interdisciplinary Institute for Neuroscience, Bordeaux, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Humeau
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Jean
authors.initials: J
authors.lastname: Pieters
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003071:Cognition / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D008568:Memory; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D012919:Social Behavior; D054378:Acetogenins
chemical_list: D015107:4-Butyrolactone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D008840:Microfilament Proteins; C438920:coronin acetogenin; D054378:Acetogenins; C072061:coronin proteins