Letter

A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice

Received:
Accepted:
Published online:

Abstract

The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging1,2. The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals3,4,5 and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower6. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated. Here we show that a low dose of Δ9-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density. THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC. Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft grants FOR926 (SP2 and CP2), BI-1227/5 and SFB645. J.L.S. and A.Z. are members of the DFG Cluster of Excellence ImmunoSensation.

Author information

Author notes

    • Andras Bilkei-Gorzo
    •  & Onder Albayram

    These authors contributed equally to this work.

Affiliations

  1. Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany.

    • Andras Bilkei-Gorzo
    • , Onder Albayram
    • , Kerstin Michel
    • , Anastasia Piyanova
    • , Ildiko Rácz
    • , Sophie Imbeault
    •  & Andreas Zimmer
  2. Genomics and Immunoregulation, LIMES Institute, Bonn, Germany.

    • Astrid Draffehn
    • , Thomas Ulas
    •  & Joachim L Schultze
  3. Institute of Dental Sciences, Hebrew University, Jerusalem, Israel.

    • Hannah Oppenheimer
    • , Mona Dvir-Ginzberg
    •  & Itai Bab

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Contributions

O.A., A.B.-G., J.L.S., M.D.-G., I.B. and A.Z. designed research; O.A., A.P., S.I., T.U., H.O., I.R., K.M., A.D. and A.B.-G. performed research; O.A., A.P., A.B.-G., T.U., J.L.S. and A.Z. analyzed data; and O.A., A.B.-G., J.L.S. and A.Z. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Andreas Zimmer.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Results, Supplementary Figures 1–10 and Supplementary Tables 2–4

  2. 2.

    Supplementary Data

    Full images of immunoblots

Excel files

  1. 1.

    Supplementary Table 1

    Ten modules identified from WGCNA, related to Supplementary Figure 7.