ArticlePhilosophical transactions of the Royal Society of London. Series B, Biological sciences2014
Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway.
Article in Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 34 citations in OpenAlex.
- Article
- Article
- Altered ClProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Neuronal Plasticity: Neuronal Organization is Associated with Neurological Disorders.Journal of molecular neuroscience : MN · 2020Review
- Rho GTPases in the Amygdala-A Switch for Fears?Cells · 2020Review
- Review
- Review
- ROCK/PKA Inhibition Rescues Hippocampal Hyperexcitability and GABAergic Neuron Alterations in a Oligophrenin-1 Knock-Out Mouse Model of X-Linked Intellectual Disability.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Rho GTPases in Intellectual Disability: From Genetics to Therapeutic Opportunities.International journal of molecular sciences · 2018Review
- Protein Kinase A Deregulation in the Medial Prefrontal Cortex Impairs Working Memory in Murine Oligophrenin-1 Deficiency.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2017Article
- Adult neurogenesis in intellectual disabilities.Oncotarget · 2017Article
- Pharmacological rescue of adult hippocampal neurogenesis in a mouse model of X-linked intellectual disability.Neurobiology of disease · 2017Article
- Rho Kinase Inhibition Is Essential During In Vitro Neurogenesis and Promotes Phenotypic Rescue of Human Induced Pluripotent Stem Cell-Derived Neurons With Oligophrenin-1 Loss of Function.Stem cells translational medicine · 2016Article
- Pathological circuit function underlying addiction and anxiety disorders.Nature neuroscience · 2014Review
- Synaptic plasticity in health and disease: introduction and overview.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2014Article
- Reduced gamma oscillations in a mouse model of intellectual disability: a role for impaired repetitive neurotransmission?PloS one · 2014Article
- Review
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Authors and funding
19 authors at 7 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
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.
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