Striatofugal balance and beneficial effects of facilitating nucleus accumbens mGlu4 receptor activity in the Fmr1-/- mouse model of Fragile X Syndrome
Abstract
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® in situ hybridization following social interaction to assess the activity of SPNs in the nucleus accumbens (NAc) and dorsal striatum. We evidenced a decrease in D1-SPN activity, biasing the D1/D2-SPN balance. We then evaluated the effects of compounds developed to repress D2-SPN activity on behavioral impairments in Fmr1-/- mice. Systemically facilitating mGlu4 or blocking A2a receptor activity relieved behavioral deficits in this model. Moreover, social interaction in Fmr1-/- mice was fully rescued by photopharmacological activation of mGlu4 in the ventral pallidum, to which both NAc D1- and D2-SPNs project, and mGlu4 receptors in the NAc likely contributed to restoring social deficits after systemic mGlu4 facilitation. Together, these results are consistent with our working hypotheses of both biased striatal D1/D2-SPN balance in social deficit and contribution of mGlu4 receptors expressed by NAc SPNs in modulating social behavior. In conclusion, pharmacological compounds able to regulate SPN activity demonstrate a promising therapeutic potential to relieve ASD-like deficits in FXS.
Related
- Early social enrichment enhances adult social investigation and increases oxytocin and vasopressin receptor mRNA expression in the nucleus accumbens of adult female mice
- Adult motivation deficits produced by early developmental fluoxetine exposure are rescued by nucleus accumbens mu opioid receptor antagonism
- Toll-like receptor 4-driven translational reprogramming in macrophages is unaffected by Salmonella SPI-1 activity
- Constitutive androgen receptor activity sustains DNA replication programs in triple-negative breast cancer.
- Pharmacological Activity of Motugivatrep, a Novel Antagonist of Transient Receptor Potential Cation Channel Subfamily V Member 1
BibTeX
@article{fonteneau2026striatofugal,
title = {{Striatofugal balance and beneficial effects of facilitating nucleus accumbens mGlu4 receptor activity in the Fmr1-/- mouse model of Fragile X Syndrome}},
author = {Mathieu Fonteneau and Claire Terrier and Florian Bolot and Fani Pantouli and Agathe Brugoux and Fanny Malhaire and Ingrid Wagnon and Roser Borràs-Tuduri and Paola Rossolillo and Isabelle Mccort-Tranchepain and Alexis Bailey and Francine Acher and Amadeu Llebaria and Cyril Goudet and Jérôme A.J. Becker and Julie Le Merrer},
journal = {Pharmacological Research},
year = {2026},
month = oct,
doi = {10.1016/j.phrs.2026.109712},
url = {https://hal.science/hal-05852251v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Striatofugal balance and beneficial effects of facilitating nucleus accumbens mGlu4 receptor activity in the Fmr1-/- mouse model of Fragile X Syndrome
AU - Mathieu Fonteneau
AU - Claire Terrier
AU - Florian Bolot
AU - Fani Pantouli
AU - Agathe Brugoux
AU - Fanny Malhaire
AU - Ingrid Wagnon
AU - Roser Borràs-Tuduri
AU - Paola Rossolillo
AU - Isabelle Mccort-Tranchepain
AU - Alexis Bailey
AU - Francine Acher
AU - Amadeu Llebaria
AU - Cyril Goudet
AU - Jérôme A.J. Becker
AU - Julie Le Merrer
PY - 2026
DA - 2026/10/29
JO - Pharmacological Research
DO - 10.1016/j.phrs.2026.109712
UR - https://hal.science/hal-05852251v1
AB - 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® in situ hybridization following social interaction to assess the activity of SPNs in the nucleus accumbens (NAc) and dorsal striatum. We evidenced a decrease in D1-SPN activity, biasing the D1/D2-SPN balance. We then evaluated the effects of compounds developed to repress D2-SPN activity on behavioral impairments in Fmr1-/- mice. Systemically facilitating mGlu4 or blocking A2a receptor activity relieved behavioral deficits in this model. Moreover, social interaction in Fmr1-/- mice was fully rescued by photopharmacological activation of mGlu4 in the ventral pallidum, to which both NAc D1- and D2-SPNs project, and mGlu4 receptors in the NAc likely contributed to restoring social deficits after systemic mGlu4 facilitation. Together, these results are consistent with our working hypotheses of both biased striatal D1/D2-SPN balance in social deficit and contribution of mGlu4 receptors expressed by NAc SPNs in modulating social behavior. In conclusion, pharmacological compounds able to regulate SPN activity demonstrate a promising therapeutic potential to relieve ASD-like deficits in FXS.
SN - 1043-6618
SN - 1096-1186
ER -