Fmr1-Deficiency Impacts Body Composition, Skeleton, and Bone Microstructure in a Mouse Model of Fragile X Syndrome

Leboucher, Antoine; Bermudez-Martin, Patricia; Mouska, Xavier; Amri, Ez-Zoubir; Pisani, Didier F.; Davidovic, Laetitia

doi:10.3389/fendo.2019.00678

Cited by 14 publications

(25 citation statements)

References 39 publications

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“…However, mGluR5 has been found to activate the mTOR pathway in hippocampal slices, a mechanism that seems to be compromised in Fragile X syndrome, 50 , 51 a condition associated with a loss of visceral adiposity. 52 It is possible then that the same pathway might be replicated also in hepatocytes, thus justifying the effects on SREBP-1 and PPAR-α expression we observed in MPEP-treated fatty hepatocytes ( Figure 6 ).…”

Section: Discussionmentioning

confidence: 57%

The selective blockade of metabotropic glutamate receptor-5 attenuates fat accumulation in an <em>in vitro</em> model of benign steatosis

Ferrigno¹,

Berardo²,

Pasqua³

et al. 2020

Eur J Histochem

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It has been previously found that the blockade of metabotropic glutamate receptor type 5 (mGluR5) protects against hepatic ischemia/reperfusion injury and acetaminophen toxicity. The role of mGluR5 in NAFLD has not yet been elucidated. Here, we evaluated the effects of mGluR5 blockade in an in vitro model of steatosis. HepG2 cells were pre-incubated for 12 h with an mGluR5 agonist, a negative allosteric modulator (DHPG and MPEP, respectively) or vehicle, then treated with 1.5 mM oleate/palmitate (O/P) for another 12 h. Cell viability was evaluated with the MTT assay; fat accumulation was measured using the fluorescent dye nile red; SREBP-1, PPAR-α, iNOS and Caspase-3 protein expression were evaluated by Western blot; NFkB activity was evaluated as pNFkB/NFkB ratio. mGluR5 modulation did not alter cell viability in O/P-incubated cells; MPEP prevented intracellular lipid accumulation in O/P treated cells; MPEP administration was also associated with a reversion of O/P-induced changes in SREBP-1 and PPAR-α expression, involved in free fatty acid (FFA) metabolism and uptake. No changes were observed in iNOS and Caspase-3 expression, or in NFkB activity. In conclusion, mGluR5 pharmacological blockade reduced fat accumulation in HepG2 cells incubated with O/P, probably by modulating the expression of SREBP-1 and PPAR-α.

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Section: Discussionmentioning

confidence: 57%

The selective blockade of metabotropic glutamate receptor-5 attenuates fat accumulation in an <em>in vitro</em> model of benign steatosis

Ferrigno¹,

Berardo²,

Pasqua³

et al. 2020

Eur J Histochem

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“…The animals followed multiple behavioral tests respecting their resting hours, with a minimum of 2 days between tests. Standard behavioral tests that have extensively been used to characterize genetic and environmental models of ASD [66][67][68][69][70] were implemented to assess the behavioral dimensions impacted in ASD. Tab.…”

Section: Behavioral Testingmentioning

confidence: 99%

“…Animals were individually placed in actimetry chambers under a 12-h light/dark cycle, with free access to food and drinking water. To avoid biases in measurements due to stress possibly inducing hyperlocomotion in a novel environment, a habituation period (day 0, 11:00 p.m.-day 1, 8:00 a.m.) preceded the 24-h recording of horizontal activity (day 1, 8:00 a.m.day 2, 8:00 a.m.) [68].…”

Section: Locomotor Activitymentioning

confidence: 99%

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The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

et al. 2021

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Background Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. Results Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. Conclusions The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.

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“…Standard behavioral tests that have extensively been used to characterize genetic and environmental models of ASD[31][32][33][34] were implemented to assess: social behavior (three-chamber sociability test, dyadic social interactions), repetitive behaviors (motor…”

mentioning

confidence: 99%

The microbial metabolitep-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

Bermudez-Martin

Becker

Caramello

et al. 2020

Preprint

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Background: Perturbations of the microbiota-gut-brain axis have been identified in autism spectrum disorders (ASD), suggesting that the microbiota could be involved in the development or maintenance of abnormal social and stereotyped behaviors in ASD patients.Yet, the underlying mediators and mechanisms remain unclear. We hypothesized that microbial metabolites produced by the gut microbiota contribute to behavioral deficits in ASD.We focused on p-Cresol, a microbial metabolite previously described as abnormally elevated in ASD patients. Methods:Wild-type mice were chronically treated with p-Cresol in drinking water to mimic intestinal exposure. We combined behavioral phenotyping, electrophysiology, microbiota 16S sequencing and fecal microbiota transplantations to decipher the consequences of p-Cresol exposure. Results:We showed that p-Cresol selectively induced behavioral alterations reminiscent of ASD core symptoms: social behavior deficits, stereotypies and perseverative behaviors, but no changes in anxiety, locomotion or cognition. We further showed that p-Cresol decreases the activity of dopamine neurons in the ventral tegmental area (VTA), a key brain region for social reward processing. In addition, we reveal that p-Cresol remodels the intestinal microbiome, impacting specific bacterial taxa associated with social behavior deficits and stereotypies. We further demonstrated that social behavior deficits are transferred to control mice after transplantation of microbiota from p-Cresol-treated mice. Finally, both social interactions and VTA dopamine neurons activity were normalized in p-Cresol treated mice after transplant of microbiota from control mice. Conclusions:Our study suggests that the microbial metabolite p-Cresol could be involved in the development of autistic behaviors through remodeling of the gut microbiota.

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Fmr1-Deficiency Impacts Body Composition, Skeleton, and Bone Microstructure in a Mouse Model of Fragile X Syndrome

Cited by 14 publications

References 39 publications

The selective blockade of metabotropic glutamate receptor-5 attenuates fat accumulation in an <em>in vitro</em> model of benign steatosis

The selective blockade of metabotropic glutamate receptor-5 attenuates fat accumulation in an <em>in vitro</em> model of benign steatosis

The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

The microbial metabolitep-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

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