Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Philosophical Transactions of the Royal Society B: Biological Sciences Année : 2014

Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway

Malik Khelfaoui
  • Fonction : Auteur
Bruno Ragazzon
  • Fonction : Auteur
Christian Müller
Bettadapura N Srikumar
  • Fonction : Auteur
Chun-Lei Zhang
  • Fonction : Auteur
Marie Kneib
  • Fonction : Auteur
Bernard Poulain
  • Fonction : Auteur
Sophie Reibel-Foisset
  • Fonction : Auteur
Nicolas Vitale
Jamel Chelly
  • Fonction : Auteur
Pierre Billuart
Andreas Lüthi
  • Fonction : Auteur
Yann Humeau

Résumé

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

Dates et versions

hal-03367917 , version 1 (10-11-2021)

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Malik Khelfaoui, Frédéric Gambino, Xander Houbaert, Bruno Ragazzon, Christian Müller, et al.. Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway. Philosophical Transactions of the Royal Society B: Biological Sciences, 2014, 369 (1633), pp.20130160. ⟨10.1098/rstb.2013.0160⟩. ⟨hal-03367917⟩
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