Lasting effects of endocannabinoids

It is generally agreed that cannabinoids disrupt learning and memory. As our understanding of the normal functions of the cannabinoid receptors and their ligands, the endocannabinoids, improves, we are starting to see why this might be so. A study by Chevaleyre and Castillo in Neuron suggests a new way for endocannabinoids to influence synaptic plasticity and might shed more light on this problem.

Previous studies have led to the idea that endocannabinoids can be released from postynaptic neurons at synapses and act as retrograde messengers, activating cannabinoid receptors (CB₁Rs) on the presynaptic neuron. For example, in the hippocampus, retrograde endocannabinoid signalling can transiently inhibit the release of γ-aminobutyric acid (GABA). The new study found that high-frequency stimulation of the stratum radiatum can cause long-term depression (LTD) of the inhibitory inputs to the pyramidal neurons, and that this effect is mediated by heterosynaptic retrograde endocannabinoid signalling.

Chevaleyre and Castillo provide evidence that this form of plasticity at inhibitory synapses, which they call I-LTD, requires activation of the glutamate receptors on the pyramidal neurons. Blocking CB₁R prevented I-LTD, as did preventing the synthesis of 2-arachidonoyl glycerol (2-AG) — one of the endogenous ligands for these receptors. The results of the study indicate that activation of the postsynaptic glutamate receptors during high-frequency stimulation causes the production of 2-AG, which heterosynaptically activates presynaptic CB₁Rs on interneurons and inhibits the release of GABA.

This reduction in inhibition of the CA1 pyramidal cells, which is long-lasting, will make the pyramidal neurons more excitable. This could contribute to the long-term potentiation (LTP) that is produced in these neurons by high-frequency stimulation such as that used by Chevaleyre and Castillo. Because chronic treatment with cannabinoids decreases the number of hippocampal CB₁Rs, it could impair the expression of I-LTD and so reduce LTP in the hippocampus. As the authors suggest, this has the potential to influence memory formation, and could help to explain the deleterious effects of cannabinoids on memory.