Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity

Neuropsychopharmacology. 2014 Aug;39(9):2049-60. doi: 10.1038/npp.2014.59. Epub 2014 Mar 12.

Abstract

The etiology of Autism Spectrum Disorders (ASDs) remains largely unknown. Identifying vulnerability genes for autism represents a major challenge in the field and allows the development of animal models for translational research. Mice lacking the mu opioid receptor gene (Oprm1(-/-)) were recently proposed as a monogenic mouse model of autism, based on severe deficits in social behavior and communication skills. We confirm this hypothesis by showing that adult Oprm1(-/-) animals recapitulate core and multiple comorbid behavioral symptoms of autism and also display anatomical, neurochemical, and genetic landmarks of the disease. Chronic facilitation of mGluR4 signaling, which we identified as a novel pharmacological target in ASDs in these mice, was more efficient in alleviating behavioral deficits than the reference molecule risperidone. Altogether, our data provide first evidence that disrupted mu opioid receptor signaling is sufficient to trigger a comprehensive autistic syndrome, maybe through blunted social reward processes, and this mouse model opens promising avenues for therapeutic innovation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggression / drug effects
  • Aggression / physiology
  • Anilides / pharmacology
  • Animals
  • Anxiety / drug therapy
  • Anxiety / pathology
  • Anxiety / physiopathology
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Brain / pathology
  • Brain / physiopathology
  • Child Development Disorders, Pervasive / drug therapy
  • Child Development Disorders, Pervasive / pathology*
  • Child Development Disorders, Pervasive / physiopathology*
  • Convulsants / pharmacology
  • Cyclohexanecarboxylic Acids / pharmacology
  • Disease Models, Animal
  • Excitatory Amino Acid Agents / pharmacology
  • Female
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Pentylenetetrazole / pharmacology
  • Receptors, Metabotropic Glutamate / metabolism*
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / metabolism*
  • Seizures / chemically induced
  • Seizures / physiopathology
  • Social Behavior

Substances

  • Anilides
  • Convulsants
  • Cyclohexanecarboxylic Acids
  • Excitatory Amino Acid Agents
  • Oprm protein, mouse
  • Receptors, Metabotropic Glutamate
  • Receptors, Opioid, mu
  • VU 0155041
  • Pentylenetetrazole
  • metabotropic glutamate receptor 4