Antagonists of mGluR5 receptors, which modulate glutamatergic neurotransmission, are in clinical trials for Fragile X syndrome, the major genetic cause of intellectual disabilities. Approximately 30% of Fragile X cases meet the diagnostic criteria for autism. To evaluate mGluR5 receptor modulation as a potential intervention target for autism, we tested a mGluR5 negative allosteric modulator in mouse models of autism.
Objectives:
Our experiments assess the preclinical efficacy of a novel mGluR5 receptor modulator, PF-05212391, as a potential intervention target for autism spectrum disorders in BTBR T+tf/J (BTBR), a mouse model of autism. BTBR displays multiple behavioral phenotypes with face validity to all three of the diagnostic symptoms of autism, including well-replicated low sociability, low levels of vocalizations in social settings, and high levels of repetitive self-grooming (Yang et al., 2009; Scattoni et al., 2010; Silverman et al., 2010). PF-05212391 was similarly tested in C58/J mice (C58), which display high levels of stereotyped jumping (Ryan et al., 2010), and a control strain, C57BL/6J (B6).
Methods:
BTBR, C58 and B6 were given an intraperitoneal injection of PF-05212391 (0.3 mg/kg, 1.0 mg/kg, or 3.0 mg/kg) or vehicle (10% Tween-80 in saline) 30 minutes before behavioral testing or collection of brain and plasma samples for pharmacokinetic and ex vivo receptor binding analyses. BTBR and B6 were tested in one of three behavioral tasks: (1) social approach in our three-chambered apparatus (Yang et al., 2011), self-grooming in a clean standard mouse cage for a 10 minute test session (Silverman et al., 2010), and open field locomotor activity as a control measure to detect confounding drug-induced behavioral sedation (Silverman et al., 2010). Number of vertical jumps in a clean mouse cage and open field locomotion were measured in C58 mice. Two cohorts of BTBR and B6 were tested at NIMH in Bethesda, MD. One cohort of BTBR and B6 and one cohort of C58 were tested at Pfizer in Groton, CT.
Results:
PF-05212391 strongly reduced repetitive self-grooming in three cohorts of BTBR mice tested in two different laboratory environments. PF-05212391 also reduced stereotyped jumping in C58 mice. Effective doses of PF-05212391 on repetitive or stereotyped behavior in BTBR or C58 mice, respectively, corresponded to 30-90% mGluR5 receptor occupancy levels in brain homogenates, and did not produce signs of sedation, as measured in the open field locomotor exploration test. Most intriguingly, PF-05212391 partially rescued the striking lack of sociability in BTBR on parameters of social approach. The relationship between free, unbound brain levels of PF-05212391 and mGluR5 occupancy were similar across all three mouse strains.
Conclusions:
Corroborative results across multiple cohorts of mice and two laboratories provide strong preclinical evidence that a novel, potent and selective mGluR5 negative allosteric modulator reduces repetitive and stereotyped behaviors in two mouse models of autism. Further, PF-05212391 improves parameters of sociability in the BTBR model. These findings raise the possibility that a single targeted pharmacological intervention may alleviate multiple diagnostic behavioral symptoms of autism.