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

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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Figure 1: Chronic, low-dose THC treatment restores learning ability in aged mice.
Figure 2: Molecular changes in the hippocampus induced by low-dose THC treatment.
Figure 3: Epigenetic changes induced by low-dose THC treatment in hippocampal tissue.
Figure 4: The effects of low-dose THC treatment in mature animals are blocked by the histone acetyltransferase inhibitor anacardic acid and are absent in mice with deletion of Cb1 in glutamatergic neurons.

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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.

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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.

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Correspondence to Andreas Zimmer.

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Supplementary Results, Supplementary Figures 1–10 and Supplementary Tables 2–4 (PDF 42541 kb)

Supplementary Table 1

Ten modules identified from WGCNA, related to Supplementary Figure 7. (XLSX 647 kb)

Supplementary Data

Full images of immunoblots (PDF 44932 kb)

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Bilkei-Gorzo, A., Albayram, O., Draffehn, A. et al. A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat Med 23, 782–787 (2017). https://doi.org/10.1038/nm.4311

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