Clozapine counteracts a ketamine-induced depression of hippocampal-prefrontal neuroplasticity and alters signaling pathway phosphorylation
Marion Rame, D. Caudal, E. Schenker, P. Svenningsson, M. Spedding, T. Jay, B. Godsil
PLoS One May 4, 2017 DOI: 10.1371/journal.pone.0177036 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | Ketamine Clozapine |
| Topics | Depression Esketamine Ketamine Neuroplasticity |
| Key findings | A low dose of ketamine depressed hippocampal-prefrontal cortex LTP, but co-administration of clozapine produced LTP similar to saline controls. Both drugs altered phosphorylation of GSK3β, mTOR, GluA1, ERK, and TrkB in region-specific patterns, suggesting these signaling pathways may mediate the drugs' opposing effects on neuroplasticity in the stress-sensitive H-PFC network. |
Abstract
Single sub-anesthetic doses of ketamine can exacerbate the symptoms of patients diagnosed with schizophrenia, yet similar ketamine treatments rapidly reduce depressive symptoms in major depression. Acute doses of the atypical antipsychotic drug clozapine have also been shown to counteract ketamine-induced psychotic effects. In the interest of understanding whether these drug effects could be modeled with alterations in neuroplasticity, we examined the impact of acutely-administered ketamine and clozapine on in vivo long-term potentiation (LTP) in the rat’s hippocampus-to-prefrontal cortex (H-PFC) pathway. We found that a low dose of ketamine depressed H-PFC LTP, whereas animals that were co-administrated the two drugs displayed LTP that was similar to a saline-treated control. To address which signaling molecules might mediate such effects, we also examined phosphorylation and total protein levels of GSK3β, GluA1, TrkB, ERK, and mTOR in prefrontal and hippocampal sub-regions. Among the statistically significant effects that were detected (a) both ketamine and clozapine increased the phosphorylation of Ser9-GSK3β throughout the prefrontal cortex and of Ser2481-mTOR in the dorsal hippocampus (DH), (b) clozapine increased the phosphorylation of Ser831-GluA1 throughout the prefrontal cortex and of Ser845-GluA1 in the ventral hippocampus, (c) ketamine treatment increased the phosphorylation of Thr202/Tyr204-ERK in the medial PFC (mPFC), and (d) clozapine treatment was associated with decreases in the phosphorylation of Tyr705-TrkB in the DH and of Try816-TrkB in the mPFC. Further analyses involving phosphorylation effect sizes also suggested Ser831-GluA1 in the PFC displayed the highest degree of clozapine-responsivity relative to ketamine. These results provide evidence for how ketamine and clozapine treatments affect neuroplasticity and signaling pathways in the stress-sensitive H-PFC network. They also demonstrate the potential relevance of H-PFC pathway neuroplasticity for modeling ketamine-clozapine interactions in regards to psychosis.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
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- Overlap and Divergence in Ketamine and Lithium Response in Bipolar Disorder: A Scoping Review Pharmaceuticals November 3, 2025
- Retracing our steps to understand ketamine in depression: A focused review of hypothesized mechanisms of action Mental Health Clinician May 1, 2021
- Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity. Neuropharmacology November 2018
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and 5 more in the library