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Philos Trans R Soc Lond B Biol Sci. 2013 Dec 2;369(1633):20130160. doi: 10.1098/rstb.2013.0160. Print 2014 Jan 5.

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

Author information

1
Centre National de la Recherche Scientifique UPR3212, CNRS, Université de Strasbourg, , Strasbourg 67084, France.

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.

KEYWORDS:

PKA; adenylate cyclase; amygdala; fasudil; presynaptic plasticity

PMID:
24298161
PMCID:
PMC3843891
DOI:
10.1098/rstb.2013.0160
[Indexed for MEDLINE]
Free PMC Article

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