Ketamine's schizophrenia-like effects are prevented by targeting PTP1B.

In mice, subanesthetic doses of ketamine produce schizophrenia-like behaviors, including hyperlocomotion and deficits in working memory and sensorimotor gating. Ketamine increased the membrane resistance and excitability of pyramidal neurons in the prefrontal cortex and reduced endocannabinoid mobilization while unexpectedly decreasing inhibitory inputs. Pharmacological inhibition of the enzyme PTP1B with Trodusquemine restored normal neuronal properties and prevented the ketamine-induced deficits in memory and sensorimotor gating, but not hyperlocomotion. Ablation of PTP1B in glutamatergic neurons similarly prevented memory and sensorimotor gating deficits but not hyperlocomotion, suggesting PTP1B in different cell types mediates distinct effects. Trodusquemine may represent a new class of fast-acting antipsychotic drugs for schizophrenia-like symptoms.

Study at a glance

Abstract

Subanesthetic doses of ketamine induce schizophrenia-like behaviors in mice including hyperlocomotion and deficits in working memory and sensorimotor gating. Here, we examined the effect of in vivo ketamine administration on neuronal properties and endocannabinoid (eCB)-dependent modulation of synaptic transmission onto layer 2/3 pyramidal neurons in brain slices of the prefrontal cortex, a region tied to the schizophrenia-like behavioral phenotypes of ketamine. Since deficits in working memory and sensorimotor gating are tied to activation of the tyrosine phosphatase PTP1B in glutamatergic neurons, we asked whether PTP1B contributes to these effects of ketamine. Ketamine increased membrane resistance and excitability of pyramidal neurons. Systemic pharmacological inhibition of PTP1B by Trodusquemine restored these neuronal properties and prevented each of the three main ketamine-induced behavior deficits. Ketamine also reduced mobilization of eCB by pyramidal neurons, while unexpectedly reducing their inhibitory inputs, and these effects of ketamine were blocked or occluded by PTP1B ablation in glutamatergic neurons. While ablation of PTP1B in glutamatergic neurons prevented ketamine-induced deficits in memory and sensorimotor gating, it failed to prevent hyperlocomotion (a psychosis-like phenotype). Taken together, these results suggest that PTP1B in glutamatergic neurons mediates ketamine-induced deficits in eCB mobilization, memory and sensorimotor gating whereas PTP1B in other cell types contributes to hyperlocomotion. Our study suggests that the PTP1B inhibitor Trodusquemine may represent a new class of fast-acting antipsychotic drugs to treat schizophrenia-like symptoms.