Cannabidiol Improves Cognitive Impairment and Reverses Cortical Transcriptional Changes Induced by Ketamine, in Schizophrenia-Like Model in Rats

Ewa Kozela; Martyna Krawczyk; Tomasz Kos; Ana Juknat; Zvi Vogel; Piotr Popik

doi:10.1007/s12035-019-01831-2

Cannabidiol Improves Cognitive Impairment and Reverses Cortical Transcriptional Changes Induced by Ketamine, in Schizophrenia-Like Model in Rats

Ewa Kozela^*, Martyna Krawczyk, Tomasz Kos, Ana Juknat, Zvi Vogel, Piotr Popik

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Cannabidiol (CBD), a non-psychotropic cannabinoid, demonstrates antipsychotic-like and procognitive activities in humans and in animal models of schizophrenia. The mechanisms of these beneficial effects of CBD are unknown. Here, we examined behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repeated ketamine (KET) administration. In parallel, we assessed transcriptional changes behind CBD activities in the prefrontal cortex (PFC), the main brain area linked to schizophrenia-like pathologies. Male Sprague-Dawley rats were injected for 10 days with KET followed by 6 days of CBD. The cognitive performance was evaluated in the novel object recognition test followed by PFC dissections for next-generation sequencing (RNA-Seq) analysis and bioinformatics. We observed that KET-induced learning deficits were rescued by CBD (7.5 mg/kg). Similarly, CBD reversed transcriptional changes induced by KET. The majority of the genes affected by KET and KET-CBD were allocated to astroglial and microglial cells and associated with immune-like processes mediating synaptogenesis and neuronal plasticity. These genes include C1qc, C1qa, C1qb, C2, and C3 complement cascade elements, Irf8 factor and Gpr84, Gpr34, Cx3cr1, P2ry12, and P2ry6 receptors. The main pathway regulators predicted to be involved included TGFβ1 and IFNγ. In addition, CBD itself upregulated oxytocin mRNA in the PFC. The present data suggest that KET induces cognitive deficits and transcriptional changes in the PFC and that both effects are sensitive to a reversal by CBD treatment.

Original language	American English
Pages (from-to)	1733-1747
Number of pages	15
Journal	Molecular Neurobiology
Volume	57
Issue number	3
DOIs	https://doi.org/10.1007/s12035-019-01831-2
State	Published - 1 Mar 2020
Externally published	Yes

Bibliographical note

Funding Information:
The RNA-Seq and bioinformatics analyzes were performed in The Crown Genomics Institute and in The Mantoux Bioinformatics Institute, respectively, of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel. Particularly, we thank Dr Sima Benjamini for technical assistance with RNA sample handling and performing RNA-Seq, and to Michael Gershovis for the core bioinformatics analysis.

Funding Information:
This work was supported by the Dr Miriam and Sheldon G. Adelson Medical Research Foundation and by the statutory funds of the Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

Cannabidiol
Cognitive impairment
Gene expression
Ketamine
Oxytocin
Schizophrenia

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10.1007/s12035-019-01831-2

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title = "Cannabidiol Improves Cognitive Impairment and Reverses Cortical Transcriptional Changes Induced by Ketamine, in Schizophrenia-Like Model in Rats",

abstract = "Cannabidiol (CBD), a non-psychotropic cannabinoid, demonstrates antipsychotic-like and procognitive activities in humans and in animal models of schizophrenia. The mechanisms of these beneficial effects of CBD are unknown. Here, we examined behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repeated ketamine (KET) administration. In parallel, we assessed transcriptional changes behind CBD activities in the prefrontal cortex (PFC), the main brain area linked to schizophrenia-like pathologies. Male Sprague-Dawley rats were injected for 10 days with KET followed by 6 days of CBD. The cognitive performance was evaluated in the novel object recognition test followed by PFC dissections for next-generation sequencing (RNA-Seq) analysis and bioinformatics. We observed that KET-induced learning deficits were rescued by CBD (7.5 mg/kg). Similarly, CBD reversed transcriptional changes induced by KET. The majority of the genes affected by KET and KET-CBD were allocated to astroglial and microglial cells and associated with immune-like processes mediating synaptogenesis and neuronal plasticity. These genes include C1qc, C1qa, C1qb, C2, and C3 complement cascade elements, Irf8 factor and Gpr84, Gpr34, Cx3cr1, P2ry12, and P2ry6 receptors. The main pathway regulators predicted to be involved included TGFβ1 and IFNγ. In addition, CBD itself upregulated oxytocin mRNA in the PFC. The present data suggest that KET induces cognitive deficits and transcriptional changes in the PFC and that both effects are sensitive to a reversal by CBD treatment.",

keywords = "Cannabidiol, Cognitive impairment, Gene expression, Ketamine, Oxytocin, Schizophrenia",

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note = "Funding Information: The RNA-Seq and bioinformatics analyzes were performed in The Crown Genomics Institute and in The Mantoux Bioinformatics Institute, respectively, of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel. Particularly, we thank Dr Sima Benjamini for technical assistance with RNA sample handling and performing RNA-Seq, and to Michael Gershovis for the core bioinformatics analysis. Funding Information: This work was supported by the Dr Miriam and Sheldon G. Adelson Medical Research Foundation and by the statutory funds of the Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland. Publisher Copyright: {\textcopyright} 2019, Springer Science+Business Media, LLC, part of Springer Nature.",

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Cannabidiol Improves Cognitive Impairment and Reverses Cortical Transcriptional Changes Induced by Ketamine, in Schizophrenia-Like Model in Rats

Abstract

Bibliographical note

Keywords

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