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

Bilkei-Gorzo A1, Albayram O1, Draffehn A2, Michel K1, Piyanova A1, Oppenheimer H3, Dvir-Ginzberg M3, Rácz I1Ulas T2, Imbeault S1, Bab I3, Schultze JL2Zimmer A1.

  1. Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany.
  2. Genomics and Immunoregulation, LIMES Institute, Bonn, Germany.
  3. Institute of Dental Sciences, Hebrew University, Jerusalem, Israel.

 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 aging. 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 animals and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower. 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.

Nat Med. 2017 Jun;23(6):782-787. doi: 10.1038/nm.4311. Epub 2017 May 8.

Key words: THC, hypocampus, memory, 2-AG, epigenetic modification, histone acetylation