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.