ROCK/PKA inhibition rescues hippocampal hyperexcitability and GABAergic neuron alterations in Oligophrenin-1 Knock-out mouse model of X-linked intellectual disability - Inserm - Institut national de la santé et de la recherche médicale Accéder directement au contenu
Article Dans Une Revue Journal of Neuroscience Année : 2020

ROCK/PKA inhibition rescues hippocampal hyperexcitability and GABAergic neuron alterations in Oligophrenin-1 Knock-out mouse model of X-linked intellectual disability

Résumé

Oligophrenin-1 (Ophn1) encodes a Rho GTPase activating protein whose mutations cause X-linked intellectual disability (XLID) in humans. Loss of function of Ophn1 leads to impairments in the maturation and function of excitatory and inhibitory synapses, causing deficits in synaptic structure, function and plasticity. Epilepsy is a frequent co-morbidity in patients with Ophn1-dependent XLID, but the cellular bases of hyperexcitability are poorly understood. Here we report that male mice knock-out (KO) for Ophn1 display hippocampal epileptiform alterations, which are associated with changes in parvalbumin-, somatostatin- and neuropeptide Y-positive interneurons. Since loss of function of Ophn1 is related to enhanced activity of Rho-associated protein kinase (ROCK) and protein kinase A (PKA), we attempted to rescue Ophn1-dependent pathological phenotypes by treatment with the ROCK/PKA inhibitor Fasudil. While acute administration of Fasudil had no impact on seizure activity, seven weeks of treatment in adulthood were able to correct electrographic, neuroanatomical and synaptic alterations of Ophn1 deficient mice. These data demonstrate that hyperexcitability and the associated changes in GABAergic markers can be rescued at the adult stage in Ophn1-dependent XLID through ROCK/PKA inhibition.Significance Statement: In this study we demonstrate enhanced seizure propensity and impairments in hippocampal GABAergic circuitry in Ophn1 mouse model of XLID. Importantly, the enhanced susceptibility to seizures, accompanied by an alteration of GABAergic markers were rescued by ROCK/PKA inhibitor Fasudil, a drug already tested on humans. Since seizures can significantly impact the quality of life of XLID patients, the present data suggest a potential therapeutic pathway to correct alterations in GABAergic networks and dampen pathological hyperexcitability in adults with XLID.
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Dates et versions

inserm-02506604 , version 1 (12-03-2020)

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Irene Busti, Manuela Allegra, Cristina Spalletti, Chiara Panzi, Laura Restani, et al.. ROCK/PKA inhibition rescues hippocampal hyperexcitability and GABAergic neuron alterations in Oligophrenin-1 Knock-out mouse model of X-linked intellectual disability: Rescue of hyperexcitability and GABAergic defects in Ophn1 KO mice. Journal of Neuroscience, 2020, pp.0462-19. ⟨10.1523/JNEUROSCI.0462-19.2020⟩. ⟨inserm-02506604⟩

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