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

Martina Sgritta; Sean W Dooling; Shelly A Buffington; Eric N Momin; Michael B Francis; Robert A Britton; Mauro Costa-Mattioli

doi:10.1016/j.neuron.2018.11.018

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.

Authors

Martina Sgritta¹, Sean W Dooling², Shelly A Buffington¹, Eric N Momin³, Michael B Francis¹, Robert A Britton⁴, Mauro Costa-Mattioli⁵

Affiliations

¹ Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
² Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
³ Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Memory and Brain Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: costamat@bcm.edu.

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
Limosilactobacillus reuteri / genetics
Limosilactobacillus reuteri / physiology*
Male
Mice
Mice, Transgenic
Microfilament Proteins
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
Microfilament Proteins
Nerve Tissue Proteins
OXTR protein, mouse
Piperidines
Receptors, Oxytocin
Shank3 protein, mouse
Picrotoxin
Valproic Acid

Grants and funding

R01 MH112356/MH/NIMH NIH HHS/United States