Biology subjects

Le Merrer, J.

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

7 recordsLinked to original sources

bioRxiv2026

Neurobiological alterations and autism-like phenotype in mice following regulatory-limit exposure to fungicides in drinking water

Neurodevelopmental conditions, including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD), have increased markedly over recent decades. This rise parallels the widespread use of agrochemicals, suggesting a contribution of environmental exposures. We hypothesize that pesticide residues may disrupt brain development and promote neurodevelopmental disorders. Here, we test whether concentrations permitted in drinking water affect brain development using a maternal exposure model in wild-type mice. Exposure to a fungicide mixture at 0.3 g/L, below the current European regulatory limit of 0.5 g/L, impairs corticogenesis and is associated with alterations in synaptic function and glutamatergic signaling. Offspring exhibit delays in sensory development, reduced social interactions, and increased stereotyped behaviors. We identify the adenosine A2A receptor as a molecular target of anilinopyrimidine fungicides. Together, these findings indicate that low-dose exposure to this fungicide mixture can induce an autism spectrum-like phenotype in the offspring.

neuroscience↗

bioRxiv2026

Tilted striatofugal balance and beneficial effects of facilitating mGlu4 receptor activity in the Fmr1-/- mouse model of Fragile X Syndrome

Fragile X Syndrome (FXS) is the leading monogenic cause of autism spectrum disorder (ASD). To date, no approved pharmacological treatment alleviates social impairments in patients with FXS. Since D1 and D2 dopamine receptor-expressing striatal projection neurons (SPNs) were shown to regulate ASD-sensitive behaviors, we explored whether the balance of activity between D1- and D2-SPNs would be biased in the Fmr1-/- mouse model of FXS. We evaluated striatal function in Fmr1-/- and Fmr1+/+ mice under pharmacological challenge and performed RNAscope(R) in situ hybridization following social interaction to assess the activity of SPNs in the nucleus accumbens (NAc) and dorsal striatum (DS). We evidenced a decrease in D1-SPN activity, biasing the D1/D2-SPN balance towards an excessive weight of D2-SPN outputs. We then evaluated the effects of compounds that repress D2-SPN activity on behavioral impairments in Fmr1-/- mice. Systemically facilitating mGlu4 or blocking A2A receptor activity relieved behavioral deficits in this model. Finally, we tested the hypothesis that a tilt of the D1/D2-SPN balance in Fmr1-/- mice may contribute to their social deficit by facilitating mGlu4 activity directly in the projection site of NAc D2-SPNs. Social interaction in Fmr1-/- mice was fully rescued by photopharmacological activation of mGlu4 in the ventral pallidum (VP), where NAc D2-SPNs project. This result supports our hypothesis of excessive D2-SPN outputs and highlights the contribution of the VP in controlling social behavior. In conclusion, pharmacological compounds that repress D2-SPN activity demonstrate a promising therapeutic potential to relieve ASD-like deficits in FXS.

neuroscience↗

bioRxiv2024

Acute, chronic and conditioned effects of intranasal oxytocin in the mu opioid receptor knockout mouse model of autism: social context matters

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behaviours. Multiple studies have highlighted the potential of oxytocin (OT) to ameliorate behavioural abnormalities in animal models and subjects with ASD. Clinical trials, however, yielded disappointing results. Our study aimed at challenging hypotheses accounting for such negative results by assessing the behavioural effects of different regimens of OT administration in the Oprm1 null mouse model of ASD. We assessed the effects of intranasal OT injected once at different doses and time points following administration, or chronically, on ASD-related behaviours in Oprm1+/+and Oprm1-/- mice. We then tested whether pairing intranasal OT injection with social experience would influence its outcome on ASD-like core symptoms, and measured gene expression in several regions of the reward/social circuit. Acute intranasal OT improved social behaviour in Oprm1-/- mice at a moderate dose (0.3 IU) shortly after administration (5 min). Effects on non-social behaviours were limited. Chronic OT at this dose maintained beneficial effects in Oprm1 null mice but was deleterious in wild-type mice. Finally, improvements in the social behaviour of Oprm1-/- mice were greater and longer lasting when OT was administered in a social context, while the expression of OT and vasopressin receptor genes, as well as marker genes of striatal projection neurons, was suppressed. Our results highlight the importance of considering dosage and social context when evaluating the effects of OT treatment in ASD. HighlightsO_LIAcute intranasal oxytocin improved social behaviour shortly after administration C_LIO_LIEffects of oxytocin on non-social behaviours were limited C_LIO_LIChronic oxytocin maintained beneficial effects in mutant mice but was deleterious in wild-type mice C_LIO_LIOxytocin triggers greater and longer-lasting improvements in social behaviour when administered within a social context C_LIO_LIChronic oxytocin suppresses the expression of its own receptor gene and key striatal neuron gene markers C_LI

animal behavior and cognition↗

bioRxiv2022

Balance between direct and indirect pathways of the nucleus accumbens controls social behavior in mice

BackgroundDeficient social interactions are a hallmark of major neuropsychiatric disorders, and cumulating evidence point to altered social reward and motivation as key underlying mechanisms in these pathologies. In the present study, we aimed at assessing the role of the two striatal projecting neuronal (SPN) populations bearing either D1R or D2R dopamine receptors (D1R- and D2R-SPNs), in modulating social behavior and other behaviors often altered in neuropsychiatric disorders. MethodsWe selectively ablated D1R- and D2R-SPNs using an inducible diphtheria toxin receptor (DTR)-mediated cell targeting strategy and assessed social behavior as well as repetitive/perseverative behavior, motor function and anxiety levels. We tested the effects of optogenetic stimulation of D2R-SPNs in the Nucleus Accumbens (NAc) and pharmacological compounds repressing D2R-SPN. ResultsTargeted deletion of D1R-SPNs in the NAc blunted social behavior in mice, facilitated skill motor learning and increased anxiety levels. These behaviors were normalized by pharmacological inhibition of D2R-SPN, which also repressed transcription in the efferent nucleus, the ventral pallidum (VP). In contrast, ablation of D1R-SPNs in the dorsal striatum had no impact on social behavior, impaired motor skill learning, and decreased anxiety levels. Deletion of D2R-SPNs in the NAc also produced motor stereotypies but facilitated social behavior and impaired skill motor learning. We mimicked excessive D2R-SPN activity by optically stimulating D2R-SPNs in the NAc and evidenced a severe deficit in social interaction that was prevented by D2R-SPN pharmacological inhibition. ConclusionsRepressing D2R-SPN activity may represent a promising therapeutic strategy to relieve social deficit in neuropsychiatric disorders.

neuroscience↗

bioRxiv2021

Chronic sodium bromide treatment relieves autistic-like behavioral deficits in three mouse models of autism

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders whose diagnosis relies on deficient social interaction and communication together with repetitive behavior. To date, no pharmacological treatment has been approved that ameliorates social behavior in patients with ASD. Based on the excitation/inhibition imbalance theory of autism, we hypothesized that bromide ions, long used as an antiepileptic medication, could relieve core symptoms of ASD. We evaluated the effects of chronic sodium bromide (NaBr) administration on autistic-like symptoms in three genetic mouse models of autism: Oprm1-/- , Fmr1-/- and Shank3{Delta}ex13-16-/- mice. We showed that chronic NaBr treatment relieved autistic-like behaviors in these three models. In Oprm1-/- mice, these beneficial effects were superior to those of chronic bumetanide administration. At transcriptional level, chronic NaBr in Oprm1 null mice was associated with increased expression of genes coding for chloride ions transporters, GABAA receptor subunits, oxytocin and mGlu4 receptor. Lastly, we uncovered synergistic alleviating effects of chronic NaBr and a positive allosteric modulator (PAM) of mGlu4 receptor on autistic-like behavior in Oprm1-/- mice. We evidenced in heterologous cells that bromide ions behave as PAMs of mGlu4, providing a molecular mechanism for such synergy. Our data reveal the therapeutic potential of bromide ions, alone or in combination with a PAM of mGlu4 receptor, for the treatment of ASDs.

neuroscience↗

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↗