19206
Decreased Akt/mTOR Pathway Is Associated with Reduced Excitatory Synaptic Marker PSD-95 and Autistic-like Behavior in Valproic Acid-Exposed Mice
Objectives: In the current study, we aimed to investigate whether maternal exposure to the anticonvulsant valproic acid (VPA), which has been associated with autism-like phenotypes in both humans and rodents, affects TrkB, mTOR and their downstream effectors including PSD-95.
Methods: Pregnant CD1 mice received a single intraperitoneal injection of 500mg/kg VPA on gestational day 12, while controls were injected with saline. Dams were weaned on postnatal day (PND) 21, and offspring’s behavior and somatosensory function were evaluated on PND29-30 in tests of nest-seeking, negative geotaxis and social interaction preference. Litters were then sacrificed and brain tissue harvested on PND30. Protein expression of TrkB, mTOR, p70S6K and PSD-95 were measured by Western blotting in the temporal/parietal neocortices of 14 VPA-exposed mice and 11 saline controls.
Results: Offspring of VPA-injected mothers had significantly decreased TrkB, mTOR, p70S6K and PSD-95 protein compared to controls. VPA-exposed mice exhibited autistic-like behavior in tests of social interaction preference, nest-seeking and negative geotaxis.
Conclusions: Our molecular results demonstrate that, similarly to human idiopathic autism, offspring of VPA-treated mothers had significantly decreased TrkB, mTOR, p70S6K and PSD-95, supporting the hypothesis that defective TrkB and mTOR via p70S6K may have adverse consequences for excitatory synapses and contribute to autistic behavior. Indeed, we determined that down-regulation of these molecules was associated with deficits in somatosensory function and social approach behaviors in VPA-exposed mice compared to saline controls. In conclusion, our findings show that the use of valproic acid in mice induces autistic-like behavior and successfully models the molecular changes we observe in human idiopathic autism, supporting the hypothesis that defective TrkB/mTOR signaling contributes to autistic traits.