Differential signaling in human cannabinoid CB₁ receptors and their splice variants in autaptic hippocampal neurons

Background and purpose:  Cannabinoids such as Δ⁹-THC, the chief psychoactive component of marijuana and hashish, primarily act via cannabinoid receptors CB₁ and CB₂ and produce characteristic behavioral effects in humans. Due to the tractability of rodent models for electrophysiological and behavioral studies, much of the work examining cannabinoid receptor action has made use of rodent cannabinoid receptors. While CB₁ is relatively well-conserved among mammals, human CB₁ (hCB₁) nonetheless differs from rCB₁ and mCB₁ at 13 residues, which may result in differential signaling. In addition, two hCB₁ splice variants (hCB_1a and hCB_1b) have been reported, diverging in their amino-termini relative to hCB₁. In this study we have examined hCB₁ signaling in neurons.

Experimental approach:  Autaptic cultured hippocampal neurons express a complete endogenous cannabinoid signaling system, with presynaptic CB₁ receptors and the ability to synthesize and degrade endocannabinoids, making them a useful model system to study cannabinoid receptor function.

Key results:  We now report that when expressed in autaptic hippocampal neurons cultured from CB₁-/- mice, hCB₁, hCB_1a, and hCB_1b signal differentially from one another and from rodent CB₁. Specifically, hCB₁ inhibits synaptic transmission poorly relative to rCB₁.

Conclusions and implications:  Our results raise the provocative possibility that cannabinoid receptor signaling in humans is quantitatively very different from that in rodents. Since the problems of marijuana and hashish abuse occur in humans, our results highlight the importance to examine hCB₁ receptors. They also invite further study of the distribution and function of hCB₁ splice variants, given their differential signaling and potential impact on human health.