Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder

Neuron. 2019 Jan 16;101(2):246-259.e6. doi: 10.1016/j.neuron.2018.11.018. Epub 2018 Dec 3.

Abstract

Currently, there are no medications that effectively treat the core symptoms of Autism Spectrum Disorder (ASD). We recently found that the bacterial species Lactobacillus (L.) reuteri reverses social deficits in maternal high-fat-diet offspring. However, whether the effect of L. reuteri on social behavior is generalizable to other ASD models and its mechanism(s) of action remains unknown. Here, we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host's gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction.

Keywords: autism; dopamine; gut-microbiota-brain axis; microbiome; oxytocin; probiotic; social behavior; vagus nerve.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Animals
  • Autism Spectrum Disorder / complications*
  • Autism Spectrum Disorder / etiology
  • Autism Spectrum Disorder / genetics
  • Benzoxazines / administration & dosage
  • Capillary Permeability / drug effects
  • Capillary Permeability / genetics
  • Central Nervous System Stimulants / pharmacology
  • Disease Models, Animal
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Exploratory Behavior / physiology
  • Gastrointestinal Microbiome / physiology
  • Humans
  • Interpersonal Relations
  • Lactobacillus reuteri / genetics
  • Lactobacillus reuteri / physiology*
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Picrotoxin / pharmacology
  • Piperidines / administration & dosage
  • Receptors, Oxytocin / genetics
  • Receptors, Oxytocin / metabolism
  • Smell / physiology
  • Social Behavior Disorders / etiology*
  • Social Behavior Disorders / therapy*
  • Valproic Acid / toxicity

Substances

  • Benzoxazines
  • Central Nervous System Stimulants
  • Dopamine Plasma Membrane Transport Proteins
  • L 371257
  • Nerve Tissue Proteins
  • OXTR protein, mouse
  • Piperidines
  • Receptors, Oxytocin
  • Shank3 protein, mouse
  • Picrotoxin
  • Valproic Acid