Each year, more candidate compounds for the treatment of autism spectrum disorder (ASD) are being explored. Recent findings in mouse models have particularly heightened excitement about potential treatments, with pharmaceutical interventions rescuing core behavioral, electrophysiological and molecular deficits in multiple mouse models of neurodevelopmental disease. A key discovery came from studies of a Rett syndrome mouse model — mice in which the MeCP2 gene is nonfunctional — that demonstrated that neurodevelopmental deficits can be genetically rescued even after critical developmental time windows have passed¹, ². These results give hope that individuals with neurodevelopmental disorders need not be treated very early in their time-course to gain some benefit from an effective therapy. We are, however, still missing a general understanding of what specific deficits can be rescued, and how quickly, in ASD and related neurodevelopmental disorders.

Jason Lerch and his colleagues from the Hospital for Sick Children in Toronto propose to use advanced in vivo brain imaging to map genetic rescue in two mouse models of autism-related neurodevelopmental disorders: in SHANK3 conditionally reversible loss-of-function mice mimicking genetic mutations seen in ASD and Phelan-McDermid syndrome, and in MeCP2 conditionally reversible loss-of-function mice mimicking Rett syndrome. The team aims to understand the spatial extent and time-course of rescue in these genetic reactivation mouse models, and to provide an in-depth examination of potential imaging biomarkers for future human clinical trials in ASD.

Specifically, Lerch and his team will image these mouse models before, during and after genetic rescue of SHANK3 or MeCP2 using a novel high-field magnetic resonance imaging (MRI) system capable of imaging multiple live mice simultaneously. Four imaging techniques, chosen to encompass a broad spectrum of phenotypes implicated in ASD, will be used to assess alterations in anatomy, water diffusion, resting-state functional activation and neurotransmitter levels. These assessments will provide important insights into how the brain responds to restored function of SHANK3 and MeCP2, enhancing our ability to estimate the impact of treatment timing on outcome, and to calibrate expectations, for ASD treatments in humans.

If symptom rescue during a successful treatment is slow, it will be imperative to have biomarkers that can gauge effectiveness early on. The imaging techniques that Lerch and his team employ in this study are almost identical to what can be done, often in a fraction of the time, in humans. Comparing the predictive power of each of the four imaging techniques in these mouse models can thus help inform the use of these imaging techniques as biomarkers and aid in the design of future human clinical trials.