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

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

doi:10.1098/rstb.2013.0160

Cited by 30 publications

(41 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We performed a rescue experiment by treatment with the clinically approved ROCK/PKA inhibitor fasudil (Khelfaoui et al, 2014, Meziane et al, 2016) and assessed whether this pharmacological strategy was able to restore the impairments in hippocampal neurogenesis.…”

Section: Resultsmentioning

confidence: 99%

Pharmacological rescue of adult hippocampal neurogenesis in a mouse model of X-linked intellectual disability

Allegra

Spalletti

Vignoli

et al. 2017

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

Oligophrenin-1 (OPHN1) is a Rho GTPase activating protein whose mutations cause X-linked intellectual disability (XLID). How loss of function of Ophn1 affects neuronal development is only partly understood. Here we have exploited adult hippocampal neurogenesis to dissect the steps of neuronal differentiation that are affected by Ophn1 deletion. We found that mice lacking Ophn1 display a reduction in the number of newborn neurons in the dentate gyrus. A significant fraction of the Ophn1-deficient newly generated neurons failed to extend an axon towards CA3, and showed an altered density of dendritic protrusions. Since Ophn1-deficient mice display overactivation of Rho-associated protein kinase (ROCK) and protein kinase A (PKA) signaling, we administered a clinically approved ROCK/PKA inhibitor (fasudil) to correct the neurogenesis defects. While administration of fasudil was not effective in rescuing axon formation, the same treatment completely restored spine density to control levels, and enhanced the long-term survival of adult-born neurons in mice lacking Ophn1. These results identify specific neurodevelopmental steps that are impacted by Ophn1 deletion, and indicate that they may be at least partially corrected by pharmacological treatment.

show abstract

Section: Resultsmentioning

confidence: 99%

Pharmacological rescue of adult hippocampal neurogenesis in a mouse model of X-linked intellectual disability

Allegra

Spalletti

Vignoli

et al. 2017

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interestingly, similar to the suppression of spine organizational defects that are induced by oligophrenin1 loss-offunction (Govek et al, 2004), the LTD effects mediated by loss of oligophrenin1 could also be fully overcome with the inhibition of ROCK with Y-27632 (Khelfaoui et al, 2009). Because any presynaptic defects could also be alleviated with the administration of the PKA and RhoA-ROCK pathway inhibitor Fasudil (Khelfaoui et al, 2013), it appears that in all cases studied thus far, the observed oligophrenin1-knockout phenotypes in fact reflect a misregulation of signaling pathways rather than functions of oligophrenin1 as a membrane-shaping factor (Fig. 3C).…”

Section: Control By Signalingmentioning

confidence: 96%

Different functional modes of BAR domain proteins in formation and plasticity of mammalian postsynapses

Kessels

Qualmann

2015

Journal of Cell Science

View full text Add to dashboard Cite

A plethora of cell biological processes involve modulations of cellular membranes. By using extended lipid-binding interfaces, some proteins have the power to shape membranes by attaching to them. Among such membrane shapers, the superfamily of Bin–Amphiphysin–Rvs (BAR) domain proteins has recently taken center stage. Extensive structural work on BAR domains has revealed a common curved fold that can serve as an extended membrane-binding interface to modulate membrane topologies and has allowed the grouping of the BAR domain superfamily into subfamilies with structurally slightly distinct BAR domain subtypes (N-BAR, BAR, F-BAR and I-BAR). Most BAR superfamily members are expressed in the mammalian nervous system. Neurons are elaborately shaped and highly compartmentalized cells. Therefore, analyses of synapse formation and of postsynaptic reorganization processes (synaptic plasticity) – a basis for learning and memory formation – has unveiled important physiological functions of BAR domain superfamily members. These recent advances, furthermore, have revealed that the functions of BAR domain proteins include different aspects. These functions are influenced by the often complex domain organization of BAR domain proteins. In this Commentary, we review these recent insights and propose to classify BAR domain protein functions into (1) membrane shaping, (2) physical integration, (3) action through signaling components, and (4) suppression of other BAR domain functions.

show abstract

“…Such changes involve alterations in synaptic strength at sensory thalamic 19 or cortical afferents 17 to BLA principal neurons, BLA inputs onto intercalated cells 88 or onto defined subtypes of CEA neurons 44 . Moreover, recent evidence from mouse genetic models for psychiatric conditions associated with anxi ety phenotypes has identified specific deficits in the function and plasticity of excitatory inputs to the amygdala and in the function of local inhibitory circuits [89][90][91][92] . In future studies, it will be important to address the cellular and synaptic specificity of diseaseassociated functional changes and to investigate whether such changes are cause or consequence in the pathophysiological processes mediating pro gression of anxiety disorders.…”

Section: Disease-associated Synaptic Plasticitymentioning

confidence: 99%

Pathological circuit function underlying addiction and anxiety disorders

2014

Self Cite

View full text Add to dashboard Cite

Current models of addiction and anxiety stem from the idea that aberrant function and remodeling of neural circuits cause the pathological behaviors. According to this hypothesis, a disease-defining experience (for example, drug reward or stress) would trigger specific forms of synaptic plasticity, which in susceptible subjects would become persistent and lead to the disease. While the notion of synaptic diseases has received much attention, no candidate disorder has been sufficiently investigated to yield new, rational therapies that could be tested in the clinic. Here we review the arguments in favor of abnormal neuronal plasticity underlying addiction and anxiety disorders, with a focus on the functional diversity of neurons that make up the circuits involved. We argue that future research must strive to obtain a comprehensive description of the relevant functional anatomy. This will allow identification of molecular mechanisms that govern the induction and expression of disease-relevant plasticity in identified neurons. To establish causality, one will have to test whether normalization of function can reverse pathological behavior. With these elements in hand, it will be possible to propose blueprints for manipulations to be tested in translational studies. The challenge is daunting, but new techniques, above all optogenetics, may enable decisive advances.

show abstract

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

Cited by 30 publications

References 58 publications

Pharmacological rescue of adult hippocampal neurogenesis in a mouse model of X-linked intellectual disability

Pharmacological rescue of adult hippocampal neurogenesis in a mouse model of X-linked intellectual disability

Different functional modes of BAR domain proteins in formation and plasticity of mammalian postsynapses

Pathological circuit function underlying addiction and anxiety disorders

Contact Info

Product

Resources

About