A decline in learning and memory frequently accompanies the normal ageing process as well as neurodegenerative disorders. However, the molecular mechanisms that underlie cognitive deficits that arise during ageing are largely uncharacterized. Bilkei-Gorzo and colleagues have recently revealed an unexpected role for the endocannabinoid system in learning and memory decline with increasing age.
Short-term exposure to cannabinoids is well known to have a negative effect on various aspects of learning and memory, and acute pharmacological blockade of the cannabinoid CB1 receptor prevents memory deficits induced by cannabinoids, enhances memory when administered in isolation and decreases memory deficits in older animals. However, the effects of long-term alterations of the endocannabinoid system on learning and memory were, until now, unknown.
Bilkei-Gorzo and colleagues investigated the effects of deleting the CB1 receptor gene Cnr1 on three tests of learning and memory — the rotarod test, which measures psychomotor skill learning; an operant conditioning paradigm, which indexes working memory, procedural learning and spatial memory; and a social recognition test — in mice of different ages. Young mice (6–7 weeks old) that lacked the Cnr1 gene performed as well as or even better than did wild-type mice on these tasks. By contrast, absence of this gene in mature mice (3–5 months old) led to striking impairments in all three measures of learning and memory compared with their age-matched controls. Their deficits were on a par with the learning and memory abilities of aged mice (14–17 months old), which were typically impaired on these tasks relative to the younger control groups, indicating that memory decline is accelerated in the absence of CB1 receptors.
Intriguingly, these impairments were correlated with neuronal loss in areas CA1 and CA3 of the hippocampus. Bilkei-Gorzo and colleagues therefore suggested that the endocannabinoid system has an important neuroprotective effect that hinges on the presence of CB1 receptors.
With an increasing ageing population, there is a growing need to develop novel ways to treat or prevent cognitive deficits. This work provides encouraging signs that the endocannabinoid system could be a potential therapeutic target for the treatment of cognitive decline during the course of ageing.
ORIGINAL RESEARCH PAPER
Bilkei-Gorzo, A. et al. Early age-related cognitive impairment in mice lacking cannabinoid CB1 receptors. Proc. Natl Acad. Sci. USA 102, 15670–15675 (2005)
Hedden, T. & Gabrieli, J. D. E. Insights into the ageing mind: a view from cognitive neuroscience. Nature Rev. Neurosci. 5, 87–96 (2004)
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Rowan, A. Accelerated ageing. Nat Rev Neurosci 6, 918 (2005). https://doi.org/10.1038/nrn1816