Abstract
Autism spectrum disorders (ASD) are highly disabling developmental disorders with a population prevalence of 1–3%. Despite a strong genetic etiology, there are no current therapeutic options that target the core symptoms of ASD. Emerging evidence suggests that dysfunction of glutamatergic signaling, in particular through metabotropic glutamate receptor 5 (mGluR5) receptors, may contribute to phenotypic deficits and may be appropriate targets for pharmacologic intervention. This study assessed the therapeutic potential of 2-methyl-6-phenylethyl-pyrididine (MPEP), an mGluR5-receptor antagonist, on repetitive and anxiety-like behaviors in the valproic acid (VPA) mouse model of autism. Mice were exposed prenatally on day E13 to VPA and assessed for repetitive self-grooming and marble burying behaviors as adults. Anxiety-like behavior and locomotor activity were measured in an open-field. VPA-exposed mice displayed increased repetitive and anxiety-like behaviors, consistent with previously published results. Across both marble burying and self-grooming assays, MPEP significantly reduced repetitive behaviors in VPA-treated mice, but had no effect on locomotor activity. These results are consistent with emerging preclinical literature that mGluR5-antagonists may have therapeutic efficacy for core symptoms of autism.
Highlights
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by repetitive and restricted patterns of behavior, reduced social interactions, and impairments in language function
Drug effects were driven by the valproic acid (VPA) group, which was significantly different between drug conditions (P,0.04, Bonferroni post-test), whereas the SAL group did not differ between vehicle and MPEP treatments (P.0.05, Bonferroni post-test)
The present study investigated the effects of the metabotropic glutamate receptor 5 (mGluR5) antagonist MPEP on measures of anxiety and stereotyped, repetitive behaviors in a mouse model relevant to autism
Summary
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by repetitive and restricted patterns of behavior, reduced social interactions, and impairments in language function. Repetitive behaviors are of particular interest because they are the strongest predictor that an early diagnosis of ASD will persist throughout the lifetime [4]. These behaviors, with a similarity to symptoms of obsessive-compulsive disorder (OCD), include stereotypic movements, repetitive play, inflexible routines, and a ritualistic insistence on sameness [5]. When such behaviors are interrupted, a child may protest or exhibit anxiety or aggression [5]. There is a strong need to develop novel therapeutic approaches that target core deficits (and pathophysiology) of autism, while limiting adverse effects
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