Biology subjects

Le Merrer, J.

Publications and source records attributed to Le Merrer, J..

2 recordsLinked to original sources

bioRxiv2020

Facilitating mGluR4 activity reverses the long-term deleterious consequences of chronic morphine exposure

BackgroundUnderstanding the neurobiological underpinnings of abstinence from drugs of abuse is critical to allow better recovery and ensure relapse prevention in addicted subjects. MethodsBy comparing the long-term transcriptional consequences of morphine and cocaine exposure, we identified the metabotropic glutamate receptor subtype 4 (mGluR4) as a promising pharmacological target in morphine abstinence. We evaluated the behavioral and molecular effects of facilitating mGluR4 activity in abstinent mice. ResultsTranscriptional regulation of marker genes of medium spiny neurons (MSNs) in the nucleus accumbens (NAc) allowed best discriminating between 4-week morphine and cocaine abstinence. Among these markers, Grm4, encoding mGluR4, displayed down-regulated expression in the caudate putamen and NAc of morphine, but not cocaine, abstinent mice. Remarkably, chronic administration of the mGluR4 positive allosteric modulator (PAM) VU0155041 (2.5 and 5 mg/kg) rescued social abilities, normalized stereotypies and anxiety and blunted locomotor sensitization in morphine abstinent mice. This treatment improved social preference but increased stereotypies in cocaine abstinent mice. Finally, the beneficial behavioral effects of VU0155041 treatment in morphine abstinent animals were correlated with restored expression of key MSN and neural activity marker genes in the NAc. ConclusionsThis study is the first report of relieving effects of a pharmacological treatment, chronic administration of the mGluR4 PAM VU0155041, on long-term deleterious consequences of morphine exposure. It illustrates the neurobiological differences between opiate and psychostimulant abstinence and points to pharmacological repression of excessive activity of D2-MSNs in the NAc as a promising therapeutic lever in drug addiction.

neuroscience↗

bioRxiv2020

Gut microbial metabolite p-Cresol promotes autistic-like behaviors in mice through remodeling of the microbiota

BackgroundAutism Spectrum Disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis resulting in changes in microbiota composition as well as 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. ResultsMice 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 levels compared to mice transplanted with the microbiota of control mice and 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. ConclusionsThe microbial metabolite p-Cresol induces ASD core behavioral symptoms in mice via a gut microbiota-dependent mechanism. Our study paves the way for therapeutic interventions targeting the microbiota to treat patients with ASD.

neuroscience↗