Targeting Somatosensory Over-Reactivity in Mouse Models of ASD

September 30, 2019

David Ginty and colleagues have identified mechanisms through which peripheral loss of ASD-associated genes affect behaviors in mice and identify a potential peripherally restricted therapy to treat tactile over-reactivity and select ASD-related behaviors.

Autism Research Initiative (SFARI)

Featuring

David Ginty

SFARI Investigator

graph for Isoguvacine rescues social behavior in ASD mouse models — Isoguvacine rescues social behavior in ASD mouse models. Chronic treatment with the peripherally restricted GABAA receptor agonist isoguvacine restores the preference for a novel mouse in a social behavior assay. Control mice (white bars), Shank3 heterozygous mice (orange bars), Mecp2 mice carrying a Rett syndrome–associated missense mutation (pink bars) and Mecp2 hemizygous null mice (red bars) were treated daily from P1 to P42 with either saline (SAL) or isoguvacine (ISO). Image from Orefice L.L. et al. (2019). Isoguvacine rescues social behavior in ASD mouse models. Chronic treatment with the peripherally restricted GABAA receptor agonist isoguvacine restores the preference for a novel mouse in a social behavior assay. Control mice (white bars), Shank3 heterozygous mice (orange bars), Mecp2 mice carrying a Rett syndrome–associated missense mutation (pink bars) and Mecp2 hemizygous null mice (red bars) were treated daily from P1 to P42 with either saline (SAL) or isoguvacine (ISO). Image from Orefice L.L. et al. (2019).

Published work supported in part by a SFARI Pilot Award to SFARI Investigator David Ginty suggests that abnormal tactile sensitivity in mouse models of ASD can be attributed to dysfunctional peripheral mechanosensory neurons, and that this aberrant sensitivity may contribute to the appearance of behaviors that are analogous to the core symptoms of ASD, including social impairments (Orefice et al., Cell, 2016).

Now, Ginty and colleagues follow up on this work by showing that this tactile oversensitivity appears in a range of ASD mouse models via distinct physiological mechanisms and that a peripherally restricted drug can improve both the tactile-related phenotypes and other behavioral abnormalities seen in these models.

In the new work — partly funded by a SFARI Research Award — the team showed that deletion of one copy of Shank3 in cells below the neck or specifically in somatosensory neurons led to a range of changes in tactile sensitivity and social behaviors that had previously been reported in mice carrying mutations in Gabrb3 or Mecp2. Despite the common phenotypes, they showed that the tactile processing changes seen in Shank3 mutant mice can be attributed to reduced expression and function of HCN channels, a mechanism distinct from the GABA_A receptor-mediated changes in presynaptic inhibition seen in the Gabrb3 and Mecp2 mutant mice.

Finally, Ginty and colleagues show that genetically restoring Shank3 or Mecp2 expression during a critical early-postnatal window is sufficient to rescue normal tactile reactivity and at least some social and anxiety-like behaviors. Moreover, treatment with a peripherally restricted GABA_A receptor agonist called ‘isoguvacine’ ameliorates tactile oversensitivity, anxiety-like behaviors and abnormalities in social behaviors. These results hold the possibility of a treatment for both the core and allied symptoms of ASD that would avoid the undesirable side effects of drugs that act via the central nervous system.