title: Pharmacological rescue of adult hippocampal neurogenesis in a mouse model of X-linked intellectual disability.
abstract: 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.
authors.affiliation: CNR Neuroscience Institute, via G. Moruzzi 1, 56124 Pisa, Italy; Laboratorio Nest, Scuola Normale Superiore, P.zza San Silvestro 12, 56127 Pisa, Italy; Accademia Nazionale dei Lincei, via della Lungara 10, 00165 Rome, Italy. Electronic address: manuela.allegra@in.cnr.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Allegra
authors.affiliation: CNR Neuroscience Institute, via G. Moruzzi 1, 56124 Pisa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Spalletti
authors.affiliation: University of Trento, Centre for Integrative Biology (CIBIO), via Sommarive 9, 38123 Povo (TN), Italy; European Brain Reasearch Institute (EBRI)-Rita Levi-Montalcini, via del Fosso di Fiorano 64, 00143 Rome, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Vignoli
authors.affiliation: CNR Neuroscience Institute, via G. Moruzzi 1, 56124 Pisa, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Azzimondi
authors.affiliation: CNR Neuroscience Institute, via G. Moruzzi 1, 56124 Pisa, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Busti
authors.affiliation: Institute Cochin, INSERM U1016, Paris Descartes University, 24 rue du Fg St Jacques, 75014 Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Billuart
authors.affiliation: University of Trento, Centre for Integrative Biology (CIBIO), via Sommarive 9, 38123 Povo (TN), Italy; European Brain Reasearch Institute (EBRI)-Rita Levi-Montalcini, via del Fosso di Fiorano 64, 00143 Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Canossa
authors.affiliation: CNR Neuroscience Institute, via G. Moruzzi 1, 56124 Pisa, Italy. Electronic address: caleo@in.cnr.it.
authors.forename: Matteo
authors.initials: M
authors.lastname: Caleo
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000378:metabolism; D004195:Disease Models, Animal; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D008607:Intellectual Disability / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; D009687:Nuclear Proteins; C498439:Ophn1 protein, mouse
keywords: Axon extension; Dendritic spines; Fasudil; Rho GTPase