Ketamine's schizophrenia-like effects are prevented by targeting PTP1B.
Zhaohong Qin, Li Zhang, Michael A. Zasloff, Alexandre F R Stewart, Hsiao-Huei Chen
Neurobiology of Disease May 17, 2021 DOI: 10.1016/j.nbd.2021.105397 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine Trodusquemine |
| Topics | Esketamine Ketamine |
| Key points | PTP1B in glutamatergic neurons mediates ketamine-induced deficits in endocannabinoid mobilization, memory, and sensorimotor gating, while PTP1B in other cell types contributes to hyperlocomotion. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 8
- KETAMIR-2, a new molecular entity and novel ketamine analog. Frontiers in Pharmacology 2025
- Lateral Septal Circuits Govern Schizophrenia-Like Effects of Ketamine on Social Behavior bioRxiv Preprint Server August 8, 2023
- Unveiling the role of single versus repeated low-dose ketamine in attenuating doxorubicin-induced chemobrain and depression in rats: differential modulation of neuroinflammation, phosphorylated GLT-1, SERT, DAT, and BDNF/TrkB signaling. Neuropharmacology June 1, 2026
- Protective Effects of Gallic Acid on Oxidative and Inflammatory Markers in the Hippocampus and Prefrontal Cortex of a Ketamine-Induced Schizophrenia-like Model. Brain Sciences June 23, 2026
- Repeated ketamine exposure induces psychotic-like behaviors in mice via DRD1-mediated phosphorylation of p-Thr34 DARPP-32 and p-Ser10 histone H3 Cell Biology and Toxicology November 25, 2025
and 3 more in the library
Cites 12
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- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia Proceedings of the National Academy of Sciences September 25, 2012
and 7 more in the library