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

Area of Science:

• Neuroscience
• Pharmacology
• Psychiatry

Background:

• Subanesthetic ketamine doses induce schizophrenia-like behaviors in mice.
• These behaviors include hyperlocomotion, working memory deficits, and impaired sensorimotor gating.
• The prefrontal cortex is implicated in ketamine's behavioral effects.

Purpose of the Study:

• To investigate ketamine's effects on neuronal properties and endocannabinoid (eCB)-dependent synaptic transmission.
• To determine the role of tyrosine phosphatase PTP1B in ketamine-induced behaviors and neuronal changes.
• To explore Trodusquemine, a PTP1B inhibitor, as a potential therapeutic agent.

Main Methods:

• In vivo ketamine administration in mice.
• Electrophysiological recordings from prefrontal cortex layer 2/3 pyramidal neurons.
• Pharmacological inhibition of PTP1B with Trodusquemine.
• Genetic ablation of PTP1B in glutamatergic neurons.

Main Results:

• Ketamine increased pyramidal neuron excitability and membrane resistance.
• Trodusquemine reversed ketamine-induced neuronal and behavioral deficits.
• Ketamine reduced eCB mobilization and inhibitory inputs, effects blocked by PTP1B manipulation.
• PTP1B ablation prevented memory and gating deficits but not hyperlocomotion.

Conclusions:

• PTP1B in glutamatergic neurons mediates ketamine-induced memory and sensorimotor gating deficits.
• PTP1B in other cell types contributes to ketamine-induced hyperlocomotion.
• Trodusquemine shows potential as a novel fast-acting antipsychotic for schizophrenia-like symptoms.