LAUSR

mGlu5 metabotropic glutamate receptors are considered as candidate drug targets in the treatment of "monogenic" forms of autism spectrum disorders (ASD), such as Fragile-X syndrome (FXS). However, despite promising preclinical data, clinical trials using mGlu5 receptor antagonists to treat FXS showed no beneficial effects. Here, we studied the expression and function of mGlu5 receptors in the striatum of adult BTBR mice, which model idiopathic forms of ASD. Both mRNA (splice variant a) and protein levels of mGlu5 receptors were considerably higher in the striatum of BTBR mice. This was associated with a greater mGlu5 receptor-mediated polyphosphoinositides (PI) hydrolysis, that was sensitive to in vivo treatment with the mGlu5 receptor negative allosteric modulator, MTEP. Striatal up-regulation of mGlu5 receptors was associated with changes in the expression of genes encoding for proteins involved in excitatory and inhibitory neurotransmission and synaptic plasticity, including Fmr1, Dlg4 (PSD-95), Shank3 (all increased), Brd4, bdnf-exon IX, Mef2c, and Arc (all increased), GriA2, Glun1, Nr2A (all increased) and Grm1 (mGlu1), Grm2 (mGlu2), GriA1 (GluA1), and Gad1 (GAD-67) (all decreased). Behaviorally, BTBR mice showed high repetitive stereotypical behaviors, including self-grooming and deficits in social interactions. Acute or repeated (5 days) injections with MTEP (10 mg/kg, i.p.) reversed the stereotyped behavior and the social interaction deficit. Similar effects were observed with the NMDA receptor blockers MK-801 or ketamine. These findings support a pivotal role of mGlu5 receptor splice variant a abnormal expression and function in adult forms of idiopathic forms of ASD and unveil novel potential targets for therapy.