Augmenting mGluR5 Activity Ameliorates Behavior Deficits in a Transgenic Rat Model of Autism Spectrum Disorder

Background: Despite the high prevalence of autism spectrum disorder (ASD), there are currently no FDA approved medications for treating the core symptoms of this neurological disorder. There is an urgent need to develop new treatment modalities in pursuit of improving the quality of life of ASD individuals and their families. A number of genes implicated in the pathophysiology of ASD converge on the metabotropic glutamate receptor 5 (mGluR5) pathway. As a proof of this concept, pharmacological enhancement of mGlu5 receptors rescues behavioral deficits in SHANK3 knockout (KO) mice. In addition, treatment of Mecp2-deficient mice with mGluR5 positive allosteric modulator (PAM), VU0462807, improves behavior defects. All these studies lay a strong foundation to explore the potential of augmenting mGluR5 activity as a potential treatment modality for ameliorating core symptoms of ASD. However, all the studies have been performed in mice that do not show complex social behavior especially during development. This is important since ASD is a developmental disorder, and modeling the impaired social behavior during development is critical in clinically relevant animal models of ASD. However, the efficacy of mGluR5 PAM in ameliorating ASD associated core symptoms has never been determined in a transgenic rat model.

Objectives: The aim of this study was to evaluate the efficacy of mGluR5 positive allosteric modulator (PAM) 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) in ameliorating behavior and communication deficits in a well-established ASD transgenic rat model.

Methods: The social interaction profiles of WT and ASD rat model were evaluated on day 8 after treatment with CDPPB (5 mg/ kg) for seven days. Vehicle treated animals or untreated ASD rats as well as WT animals served as the control group.

Results: We observed that treatment of transgenic ASD rats with CDPPB improves social deficits compared to vehicle or untreated animals on day 8 post-administration. These results are in agreement with previous studies demonstrating the efficacy of mGluR5 agonists in ameliorating behavioral deficits in ASD mouse models.

Conclusions: The results of our study argue to explore the efficacy of mGluR5 agonists in developing novel therapeutic strategies for ameliorating core symptoms of ASD. The availability of new treatment modalities will help in improving quality of life of ASD individuals and their families.