Inhibition of Striatal-Enriched Protein Tyrosine Phosphatase (STEP) Activity Reverses Behavioral Deficits in a Rodent Model of Autism

Abstract

Highlights• In utero Valproic acid administration to pregnant mice leads to increased STEP-61 protein expression in the pups.• Elevated STEP-61 activity leads to dephosphorylation of GluN2B, Pyk2 and ERK1/2 and might play a role in autistic phenotype observed in VPA exposed pups.• STEP inhibitor, TC-2153 rescued the autistic like behavioral phenotypes in the VPA exposed pups. AbstractAutism spectrum disorders (ASDs) are highly prevalent childhood illnesses characterized by impairments in communication, social behavior, and repetitive behaviors. Studies have found aberrant synaptic plasticity and neuronal connectivity during the early stages of brain development and have suggested that these contribute to an increased risk for ASD. STEP is a protein tyrosine phosphatase that regulates synaptic plasticity and is implicated in several cognitive disorders. Here we test the hypothesis that STEP may contribute to some of the aberrant behaviors present in the VPA-induced mouse model of ASD. In utero VPA exposure of pregnant dams results in autistic-like behavior in the pups, which is associated with a significant increase in the STEP expression in the prefrontal cortex. The elevated STEP protein levels are correlated with increased dephosphorylation of STEP substrates GluN2B, Pyk2 and ERK, suggesting upregulated STEP activity. Moreover, pharmacological inhibition of STEP rescues the sociability, repetitive and abnormal anxiety phenotypes commonly associated with ASD.These data suggest that STEP may play a role in the VPA model of ASD and STEP inhibition may have a potential therapeutic benefit in this model. We thank Marija Kamceva for technical support and other laboratory members for helpful discussions. Author contributions MC, PKK and PJL conceived of and designed the experiments. JX and PKK performed drug injections and biochemistry. MC and PS performed in vivo drug administration and behavior experiments. MC, PKK and PJL interpreted the data. MC, JX, PKK and PJL helped write the manuscript. All authors approved the final version of the submitted manuscript.