title: Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway.
abstract: Loss-of-function mutations in the gene encoding for the RhoGAP protein of oligophrenin-1 (OPHN1) lead to cognitive disabilities (CDs) in humans, yet the underlying mechanisms are not known. Here, we show that in mice constitutive lack of Ophn1 is associated with dysregulation of the cyclic adenosine monophosphate/phosphate kinase A (cAMP/PKA) signalling pathway in a brain-area-specific manner. Consistent with a key role of cAMP/PKA signalling in regulating presynaptic function and plasticity, we found that PKA-dependent presynaptic plasticity was completely abolished in affected brain regions, including hippocampus and amygdala. At the behavioural level, lack of OPHN1 resulted in hippocampus- and amygdala-related learning disabilities which could be fully rescued by the ROCK/PKA kinase inhibitor fasudil. Together, our data identify OPHN1 as a key regulator of presynaptic function and suggest that, in addition to reported postsynaptic deficits, loss of presynaptic plasticity contributes to the pathophysiology of CDs.
authors.affiliation: Centre National de la Recherche Scientifique UPR3212, CNRS, Université de Strasbourg, , Strasbourg 67084, France.
authors.forename: Malik
authors.initials: M
authors.lastname: Khelfaoui
authors.forename: Frédéric
authors.initials: F
authors.lastname: Gambino
authors.forename: Xander
authors.initials: X
authors.lastname: Houbaert
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.forename: Mario
authors.initials: M
authors.lastname: Carta
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lanore
authors.forename: Bettadapura N
authors.initials: BN
authors.lastname: Srikumar
authors.forename: Philippe
authors.initials: P
authors.lastname: Gastrein
authors.forename: Marilyn
authors.initials: M
authors.lastname: Lepleux
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Zhang
authors.forename: Marie
authors.initials: M
authors.lastname: Kneib
authors.forename: Bernard
authors.initials: B
authors.lastname: Poulain
authors.forename: Sophie
authors.initials: S
authors.lastname: Reibel-Foisset
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vitale
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Pierre
authors.initials: P
authors.lastname: Billuart
authors.forename: Andreas
authors.initials: A
authors.lastname: Lüthi
authors.forename: Yann
authors.initials: Y
authors.lastname: Humeau
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003213:Conditioning, Psychological; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics; D004558:Electric Stimulation; D020690:GTPase-Activating Proteins / Q000172:deficiency* / Q000235:genetics; D007859:Learning Disabilities / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics; D017729:Presynaptic Terminals / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C498439:Ophn1 protein, mouse; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: PKA; adenylate cyclase; amygdala; fasudil; presynaptic plasticity