Utility of Rodent Mutants with Altered Synaptic Signaling Pathways to Test Possible Pharmacological Interventions for ASD

Background:  The lack of robust and replicable animal models of ASD has hindered progress in the development of effective therapeutic interventions for ASD. Recent advances in understanding the neurobiology underlying ASD led to the generation of novel animal models with high construct validity, based on gene mutations and altered CNVs reported in patients suffering from ASD, including those with mutations of genes involved in the formation of neuronal networks and synaptic plasticity. Common to these genetic models are abnormalities in glutamatergic and/or GABAergic systems.

Objectives:  One goal of EU-AIMS (European Autism Interventions - A Multicentre Study for Developing New Medications), a public-private partnership within the context of the EU's Innovative Medicines Initiative, is to develop and validate novel mouse and rat models to facilitate the advancement of novel therapies to treat ASD. We hypothesized that compounds acting at glutamatergic or GABAergic mechanisms might be efficacious to (partially) reverse abnormalities seen in these rodent models.

Methods:   A strong focus within the EU-AIMS consortium has been the phenotypic characterization of behavioral, electrophysiological and morphological alterations in KO mice and rats lacking functional cell adhesion molecules (neurexin/neuroligins) and rodents lacking functional shank proteins. Behavioral testing focused on both key ASD-related symptoms and cognitive function, including novel, touch-screen-based tests of cognitive flexibility. Because glutamatergic abnormalities have been described in some of these models, we have started to evaluate the effects of compounds acting at glutamatergic mechanisms in those models, including compounds acting at group I mGluRs.

Results:  The talk will cover the characterization of the rodent models. We will discuss behavioral data from these animals, with special emphasis on cognitive deficits and their potential translational value for the clinic. We will further show EEG and fMRI data and relate them to clinical observations. For example, structural and functional MRI revealed altered brain volume and neural activity in NLGN3 KO rats, and an altered E/I balance was seen in MRS in these animals. In NLGN3 KO mice, an up-regulation of mGluR1 was observed and we will present first data from pharmacological intervention studies, leading to partial rescue of phenotypical abnormalities in these mice.

Conclusions:  Behavioral abnormalities, as well as electrophysiological and morphological alterations (e.g., increased repetitive behavior, impaired social interaction, cognitive deficits, changes in neural activity and biochemistry) observed in at least some models are in line with alterations reported in ASD patients, suggesting good face validity on top of high construct validity. These phenotypes are accompanied by altered glutamatergic function. The preliminary pharmacological intervention studies suggest that these models are of utility for drug development. Whether there is also good predictive validity will only be addressed conclusively once efficacy readouts from the animal models have been successfully shown to translate to the clinic. Importantly, this translational aspect is currently addressed in the clinical work-packages of EU-AIMS, making this a powerful consortium to address the unmet medical needs of ASD patients.