A TrkB Partial Agonist Rescues Autistic-like Behaviors in Adult Mice Prenatally Exposed to Valproic Acid
Objectives: We examined whether increasing Akt signaling using the TrkB partial agonist LM22A-4 would restore Akt deficits and ameliorate autistic-like behavior in adult mice prenatally exposed to VPA.
Methods: Pregnant females received a single intraperitoneal (i.p.) injection of 500 mg/kg VPA on gestational day 12.5, while controls were injected with saline. Pups were weaned on postnatal day (PD) 21 and received an i.p. injection of either saline or LM22A-4 dissolved in saline (0.05 mg/g) once daily from PDs 21-35. Sociability and repetitive digging were evaluated on PDs 29-34 using the three-chambered social approach task and marble-burying test, respectively. Litters were killed and brain tissue harvested on PD 35. Akt protein and phosphorylation levels were measured by Western blotting in temporal/parietal neocortex.
Results: Adult mice prenatally exposed to VPA lacked sociability, exhibited increased repetitive digging behavior and had decreased cortical phosphorylated Akt. We demonstrated that treatment of prenatally VPA-exposed, adult mice with LM22A-4 restored sociability and decreased repetitive behavior. Additionally, LM22A-4 treatment together with enrichment from behavioral testing normalized cortical Akt phosphorylation.
Conclusions: Our results show that the TrkB partial agonist LM22A-4 rescues autistic-like behaviors in adult mice prenatally exposed to valproic acid, supporting the hypothesis that reduced Akt signaling contributes to autistic behavior, and that LM22A-4 has potential for treating sociability and repetitive/perseverative behavior in idiopathic autism.