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.

ROCK/PKA Inhibition Rescues Hippocampal Hyperexcitability and GABAergic Neuron Alterations in a Oligophrenin-1 Knock-Out Mouse Model of X-Linked Intellectual Disability

“…Since the Ophn1 gene is located on X chromosome, only male mice were used for our experiments because they develop X-linked ID, while females are not-affected carriers. The genotype was revealed through polymerase chain reaction (PCR) analysis on small samples of tail tissue taken from pups at post-natale stage P10, as described by Khelfaoui et al (2007) and Allegra et al (2017).…”

“…Ophn1 knock-out (KO) mice represent an excellent model of Ophn1 mutations in humans (Khelfaoui et al, 2007). These mice exhibit impairments in spatial memory and social behavior, 3 alterations in adult neurogenesis, and defects in dendritic spines associated with altered synaptic plasticity (Khelfaoui et al, 2013;Meziane et al, 2016;Redolfi et al, 2016;Allegra et al, 2017;Zhang et al, 2017).…”

“…Lack of Ophn1 leads to high level of ROCK/PKA activity, and several pathological deficits of Ophn1 KO mice are at least partially rescued by treatment with ROCK/PKA inhibitor Fasudil (Khelfaoui et al, 2013;Meziane et al, 2016;Redolfi et al, 2016;Allegra et al, 2017), an isoquinoline derivative drug approved for use in humans in China and Japan, and currently tested in multiple clinical trials in the United States and Europe.…”

Differential roles of pyramidal and fast-spiking, GABAergic neurons in the control of glioma cell proliferation

“…While mCherry staining was detectable in coronal sections without any amplification step, parvalbumin immunolabelling was performed with a primary guinea pig polyclonal antibody (1:500; SySy, Germany) as described (Busti et al, 2020). Counts of double labelled cells were performed using Neurolucida software (Allegra et al, 2017).…”

Rho GTPases in Intellectual Disability: From Genetics to Therapeutic Opportunities

“…Allegra et al [ 216 ] examined the survival, axonogenesis and spinogenesis of hippocampal neurons of Ophn-1 −/y mice upon treatment with fasudil. In Ophn-1 −/y mice a deficit in neuronal survival has been observed in newborn animals, while proliferation of stem/progenitor cells appears normal.…”