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

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

doi:10.1016/j.neuron.2018.11.018

Cited by 588 publications

(525 citation statements)

References 104 publications

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“…Microbes residing in the GI tract regulate mood and behavior via the microbiota-gut-brain axis [Cryan & O'Mahony, 2011;Foster & McVey Neufeld, 2013]. Several studies have shown altered microbial signatures in ASD patient populations [Luna et al, 2017;Mayer et al, 2014] and report dysbiosis in rodent models demonstrating ASD relevant behaviors [de Theije et al, 2014;Hsiao et al, 2013;Sgritta et al, 2019]. We therefore assessed whether GI dysfunction could potentially impact the structure and function of fecal microbes in NL3 R451C mice.…”

Section: Introductionmentioning

confidence: 99%

Gastrointestinal dysfunction in patients and mice expressing the autism‐associated R451C mutation in neuroligin‐3

et al. 2019

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Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin‐3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin‐3 R451C missense mutation (NL3 R451C ). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3 R451C compared to wild‐type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABA A receptor modulation in NL3 R451C mice, a well‐established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3 R451C mice. Although we observed altered sensitivity to GABA A receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA‐immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3 R451C mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3 R451C mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043–1056 . © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism‐associated R451C mutation encoding the neuroligin‐3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin‐3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication.

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Section: Introductionmentioning

confidence: 99%

Gastrointestinal dysfunction in patients and mice expressing the autism‐associated R451C mutation in neuroligin‐3

et al. 2019

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“…After being given vitamin B6, autistic children439 have a reduced urinary homovanillic acid, which suggests an improved 440 dopamine metabolism(Lelord et al, 1978). These studies suggest the 441 regulated role of vitamin B6 in dopaminergic metabolites in ASD patients.442Previously, Sgritta reported the modulated VTA plasticity by Lactobacillus 443 reuteri in ASD mouse models(Sgritta et al, 2019). Here, our study showed a444 new regulatory role of gut microbiota on dopamine in PFC by modulating 445 vitamin B6 in EphB6-deficient mice.…”

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confidence: 54%

EphB6 regulates social behavior through gut microbiota-mediated vitamin B6 metabolism and excitation/inhibition balance of medial prefrontal cortex in mice

Liu¹,

Luo

Hu³

et al. 2019

Preprint

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28Autism spectrum disorder (ASD) is a developmental disorder with no effective 29 pharmacological treatments so far. Gut microbiota has been suggested to 30 contribute to autistic symptoms. However, the key genes and the mechanisms 31 linking gut microbiota and brain dysfunctions in ASD are still unclear. Here, 32 we found deletion of EphB6, an ASD-associated candidate gene, induced 33 dysregulated gut microbiota and autism-like behavior in mice. More 34 importantly, transplanting fecal microbiota from EphB6-deficient mice resulted 35 in disturbed gut microbiota and autism-like behavior in antibiotics-treated 36 C57BL/6J mice. Meanwhile, transplanting fecal microbiota from wild-type mice 37 ameliorated disturbed gut microbiota and autism-like behavior in mice with 38 deletion of EphB6. At the metabolic levels, dysregulated gut microbiota led to 39 vitamin B6 and dopamine defects in EphB6-deficient mice. At the cellular 40 levels, excitation/inhibition (E/I) imbalance in medial prefrontal cortex was 41 induced by gut microbiota-mediated defects of vitamin B6 metabolism in 42 EphB6-deficient mice. Our study uncovers a key role for EphB6 in regulation 43 of social behavior by gut microbiota-mediated vitamin B6 metabolism, 44 dopamine synthesis and E/I balance, suggesting a new strategy for treatment 45 of ASD patients. 46 47 48 51 Autism spectrum disorder (ASD), affecting approximately 1% of the population 52 around the world, is mainly characterized with impaired social interaction and 53 communication, and restricted and repetitive behavior (Lord, Elsabbagh, Baird, 54 & Veenstra-Vanderweele, 2018). So far, only early behavioral and educational 55 interferences show ameliorative effects on autistic symptoms of ASD patients 56 and there are no effective pharmacological therapies for the treatment of core 57 autistic symptoms (Lord et al., 2018). 58 It is generally considered that ASD is caused by genetic, developmental 59 and environmental factors. And the genetic factor is considered to be the most 60 important cause of ASD. With the development of sequencing technique, 61 more and more genes have been found to be related with ASD. 62 EphB6, belonging to the Eph family of receptor tyrosine kinases, plays an 63 important role in regulating Eph receptor signaling networks, T cell functions, 64 development of intestinal epithelium and epithelial homeostasis (Luo, Yu, 65

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“…Germ‐free rodents typically exhibit deficits in both sociability and memory for social stimuli (indexed by preference for a novel social partner; Buffington et al, ; Desbonnet et al, ; Sgritta et al, ; Stilling et al, ; but see also Arentsen et al, ). Similar effects are observed following antibiotic depletion of the microbiota during development (Degroote et al, ; Desbonnet et al, ), while administration of certain probiotic species can enhance social behavior in various murine models of autism (Buffington et al, ; Hsiao et al, ; Sgritta et al, ) and inflammation‐induced social withdrawal (D'Mello et al, ). In fruit flies ( Drosophila melanogaster ), both developing and mature individuals rely on microbiota‐derived volatile compounds as social signals, influencing food and mating preference (Sharon et al, ; Venu et al, ).…”

Section: Evidence For Microbial Modulation Of Neurocognitive Developmentmentioning

confidence: 99%

“…Lesion of the vagus nerve prevents the behavioral effects of certain probiotics (Bravo et al, 2011;Sgritta et al, 2019). Most recently, it was shown that vagotomy at weaning prevented the rescue of social behavior by probiotic treatment in a genetic mouse model of autism (Sgritta et al, 2019).…”

Section: The Vagus Nervementioning

confidence: 99%

Annual Research Review: Critical windows – the microbiota–gut–brain axis in neurocognitive development

Cowan

Dinan

Cryan

2019

Child Psychology Psychiatry

128

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The gut microbiota is a vast, complex, and fascinating ecosystem of microorganisms that resides in the human gastrointestinal tract. As an integral part of the microbiota–gut–brain axis, it is now being recognized that the microbiota is a modulator of brain and behavior, across species. Intriguingly, periods of change in the microbiota coincide with the development of other body systems and particularly the brain. We hypothesize that these times of parallel development are biologically relevant, corresponding to ‘sensitive periods’ or ‘critical windows’ in the development of the microbiota–gut–brain axis. Specifically, signals from the microbiota during these periods are hypothesized to be crucial for establishing appropriate communication along the axis throughout the life span. In other words, the microbiota is hypothesized to act like an expected input to calibrate the development of the microbiota–gut–brain axis. The absence or disruption of the microbiota during specific developmental windows would therefore be expected to have a disproportionate effect on specific functions or potentially for regulation of the system as a whole. Evidence for microbial modulation of neurocognitive development and neurodevelopmental risk is discussed in light of this hypothesis, finishing with a focus on the challenges that lay ahead for the future study of the microbiota–gut–brain axis during development.

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

Cited by 588 publications

References 104 publications

Gastrointestinal dysfunction in patients and mice expressing the autism‐associated R451C mutation in neuroligin‐3

Gastrointestinal dysfunction in patients and mice expressing the autism‐associated R451C mutation in neuroligin‐3

EphB6 regulates social behavior through gut microbiota-mediated vitamin B6 metabolism and excitation/inhibition balance of medial prefrontal cortex in mice

Annual Research Review: Critical windows – the microbiota–gut–brain axis in neurocognitive development

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