Ketamine's schizophrenia-like effects are prevented by targeting PTP1B.
Neurobiology of Disease May 17, 2021 Zhaohong Qin, Li Zhang, Michael A. Zasloff et al.
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.