Ketamine preserves perineuronal nets in chronic stressed mice brain through the inhibition of microglia activation

09/08/2026

AI Summary

Ketamine rapidly alleviates depression-like behaviour in chronic restraint stress mice.
Ketamine attenuates CRS-induced reduction of WFA-positive perineuronal nets in hippocampus and medial prefrontal cortex.
Ketamine reduces IBA1-positive microglia, indicating microglia-mediated remodelling of PNNs rather than altered PNN enzyme or PV and c-Fos expression.

AI Summary

To gain insight on the mechanism underlying the antidepressant-like effects of ketamine, we focused on perineuronal nets (PNNs), an extracellular matrix structure that surrounds fast-spiking parvalbumin-positive interneurons and regulates synaptic plasticity, whose integrity is known to be compromised under stress-induced depressive conditions.

RESULTS: We found that ketamine effectively alleviated the animals' depression like behavior as well as attenuates CRS-induced reduction of WFA-positive cells in the hippocampus and medial prefrontal cortex of mice.

Basic summary

IBRO Neurosci Rep. 2026 Jul 26;21:386-400. doi: 10.1016/j.ibneur.2026.07.016. eCollection 2026 Dec.

ABSTRACT

BACKGROUND: Deeper understanding of ketamine’s mechanism of action would contribute to the discovery of novel therapeutic targets with fast-onset actions. To gain insight on the mechanism underlying the antidepressant-like effects of ketamine, we focused on perineuronal nets (PNNs), an extracellular matrix structure that surrounds fast-spiking parvalbumin-positive interneurons and regulates synaptic plasticity, whose integrity is known to be compromised under stress-induced depressive conditions.

METHODS: We first performed the description of the plastic remodeling of PNNs in the Chronic restraint stress (CRS) mice treated or un-treated with ketamine, by quantifying the number of WFA, marker of PNNs, parvalbumin (PV) and c-Fos positive cells, as a surrogate of neuronal activity. And then, we investigated the the transcripts of a number of proteins involved in the formation or degradation of PNNs with or without ketamine in CRS mice. Next, we evaluated the expression of IBA1, a microglial marker, in the hippocampus and medial prefrontal cortex after CRS treated or un-treated with ketamine.

RESULTS: We found that ketamine effectively alleviated the animals’ depression like behavior as well as attenuates CRS-induced reduction of WFA-positive cells in the hippocampus and medial prefrontal cortex of mice. Although ketamine treatment had little or no effect on the number of PV, c-Fos positive cells and the transcripts of proteins involved in the formation or degradation of PNNs. Notably, ketamine treatment lead to remarkably reduced the number of IBA1-positive cells in the hippocampus and medial prefrontal cortex after CRS.

CONCLUSION: Our findings suggest that PNNs is characterized by region-specific changes in chronic stress mouse brain and provide extensive evidence that ketamine exposure initiates microglia to remodel PNN, instead of the PNN accumulation and degradation enzymes.

PMID:42571376 | PMC:PMC13452158 | DOI:10.1016/j.ibneur.2026.07.016

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