Neuron
Volume 93, Issue 6, 22 March 2017, Pages 1375-1387.e2
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Article
Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling

https://doi.org/10.1016/j.neuron.2017.02.025Get rights and content
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Highlights

  • The endocannabinoid 2-AG speeds firing of isolated dopamine neurons

  • 2-AG inhibits A-type potassium current (IA) independent of cannabinoid receptors

  • 2-AG alters A-type potassium channel gating through a membrane lipid interaction

  • Gq/11PCR activation inhibits IA by mobilizing endogenous 2-AG in the same cell

Summary

The major endocannabinoid in the mammalian brain is the bioactive lipid 2-arachidonoylglycerol (2-AG). The best-known effects of 2-AG are mediated by G-protein-coupled cannabinoid receptors. In principle, 2-AG could modify neuronal excitability by acting directly on ion channels, but such mechanisms are poorly understood. Using a preparation of dissociated mouse midbrain dopamine neurons to isolate effects on intrinsic excitability, we found that 100 nM 2-AG accelerated pacemaking and steepened the frequency-current relationship for burst-like firing. In voltage-clamp experiments, 2-AG reduced A-type potassium current (IA) through a cannabinoid receptor-independent mechanism mimicked by arachidonic acid, which has no activity on cannabinoid receptors. Activation of orexin, neurotensin, and metabotropic glutamate Gq/11-linked receptors mimicked the effects of exogenous 2-AG and their actions were prevented by inhibiting the 2-AG-synthesizing enzyme diacylglycerol lipase α. The results show that 2-AG and related lipid signaling molecules can directly tune neuronal excitability in a cell-autonomous manner by modulating IA.

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Present address: Intramural Research Program, Synaptic Plasticity Section, National Institute on Drug Abuse, Baltimore, MD 21224, USA

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