Striatofugal balance and beneficial effects of facilitating nucleus accumbens 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® 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. 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. Pharmacological compounds ADX88178 (CAS 1235318-89-4); haloperidol hydrochloride (CAS 1511-16-6); istradefylline (CAS 155270-99-8); LSP4-2022 (CAS 1413405-33-0); morphine hydrochloride (CAS 6055-06-7); quinpirole hydrochloride (CAS 85798-08-9); SCH-23390 hydrochloride (CAS 125941-87-9); SKF-81297 hydrobromide (CAS 67287-39-2); sulpiride (CAS 15676-16-1); VU0155041 sodium (CAS 1259372-69-4); optogluram (CAS 1627840-48-5)