Loss of functionmutations in human Oligophrenin1 (OPHN1) gene are responsible for syndromic intellectual disability (ID) associated with cerebellar hypoplasia and cerebral ventricles enlargement. Functional studies in rodentmodels suggest that OPHN1 linked ID is a consequence of abnormal synaptic transmission and shares common pathophysiologicalmechanisms with other cognitive disorders. Variants of this gene have been also identified in autismspectrumdisorder and schizophrenia. The advanced understanding of themechanisms underlying OPHN1-related ID, allowed us to develop a therapeutic approach targeting the Ras homolog gene family, member A (RHOA) signalling pathway and repurpose Fasudil-a well-tolerated Rho Kinase (ROCK) and Protein Kinase A (PKA) inhibitor-as a treatment of ID. We have previously shown ex-vivo its beneficial effect on synaptic transmission and plasticity in amousemodel of the OPHN1 loss of function. Here, we report that chronic treatment in adultmouse with Fasudil, is able to counteract vertical and horizontal hyperactivities, restores recognitionmemory and limits the brain ventricular dilatation observed in Ophn1-/y. However, deficits in working and spatialmemories are partially or not rescued by the treatment. These results highlight the potential of Fasudil treatment in synaptopathies and also the need for multiple therapeutic approaches especially in adult where brain plasticity is reduced.
ASJC Scopus subject areas
- Molecular Biology