mGluR5-antagonist mediated reversal of elevated stereotyped, repetitive behaviors in the VPA model of autism.
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.
Translational Neuroscience Program, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Mili V
MV
Mehta
Michael J
MJ
Gandal
Steven J
SJ
Siegel
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use; D001321:Autistic Disorder / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D006120:Grooming / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011247:Pregnancy; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013239:Stereotyped Behavior / Q000187:drug effects*; D014635:Valproic Acid / Q000009:adverse effects*
D014151:Anti-Anxiety Agents; C578936:Grm5 protein, mouse; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D014635:Valproic Acid; C121465:6-methyl-2-(phenylethynyl)pyridine