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

Malik Khelfaoui | Zendy; Frédéric Gambino | Zendy; Xander Houbaert | Zendy; Bruno Ragazzon | Zendy; Christian Müller | Zendy; Mario Carta | Zendy; Frédéric Lanore | Zendy; Bettadapura N. Srikumar | Zendy; Philippe Gastrein | Zendy; Marilyn Lepleux | Zendy; Chun-Lei Zhang | Zendy; Marie Kneib | Zendy; Bernard Poulain | Zendy; Sophie Reibel-Foisset | Zendy; Nicolas Vitale | Zendy; Jamel Chelly | Zendy; Pierre Billuart | Zendy; Andreas Lüthi | Zendy; Yann Humeau | Zendy

Open Access

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

Author(s) -

Malik Khelfaoui,

Frédéric Gambino,

Xander Houbaert,

Bruno Ragazzon,

Christian Müller,

Mario Carta,

Frédéric Lanore,

Bettadapura N. Srikumar,

Philippe Gastrein,

Marilyn Lepleux,

Chun-Lei Zhang,

Marie Kneib,

Bernard Poulain,

Sophie Reibel-Foisset,

Nicolas Vitale,

Jamel Chelly,

Pierre Billuart,

Andreas Lüthi,

Yann Humeau

Publication year - 2013

Publication title -

philosophical transactions of the royal society b biological sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.753

H-Index - 272

eISSN - 1471-2970

pISSN - 0962-8436

DOI - 10.1098/rstb.2013.0160

Subject(s) - neuroscience , protein kinase a , excitatory postsynaptic potential , postsynaptic potential , synaptic plasticity , regulator , hippocampus , amygdala , microbiology and biotechnology , dendritic spine , biology , inhibitory postsynaptic potential , kinase , gene , biochemistry , receptor , hippocampal formation

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.

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