Biology subjects

Fonteneau, M.

Publications and source records attributed to Fonteneau, M..

3 recordsLinked to original sources

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↗