A TrkB Partial Agonist Rescues Autistic-like Behaviors in Adult Mice Prenatally Exposed to Valproic Acid

Background:  The molecular mechanisms underlying autistic behavior remain to be elucidated. We previously demonstrated reduced TrkB and Akt protein expression in postmortem fusiform gyrus tissue from human idiopathic autism. Similarly, total and phosphorylated Akt protein are decreased in cortical tissue from rats prenatally exposed to valproic acid (VPA), a well-established model of environmental/epigenetic origins of autism. These findings implicate defective TrkB signaling through Akt as a molecular substrate of autistic behavior and a potential therapeutic target for autism.

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.