The lipid signalling mechanisms that influence neuronal excitability are not well understood. Gantz and Bean show that the endocannabinoid 2-arachidonoylglycerol (2-AG; a lipid signalling molecule) can affect the intrinsic excitability of midbrain dopamine neurons through direct influence on the A-type potassium current (IA).
The authors used acutely isolated dopamine neurons from mouse substantia nigra pars compacta (SNc), which exhibit tonic firing. In vivo, these neurons also exhibit bursts of higher-frequency activity in response to reward-related cues. Ex vivo, application of 2-AG increased both the rate of intrinsic firing activity and the rate of current-injection-evoked activity. The increase in firing frequency resulted from decreased afterhyperpolarization along with more rapid depolarization to the next action potential.
Midbrain dopamine neurons have a strong IA that is mediated by voltage-gated Kv4.3 channels, which contributes to their slow rhythmic firing; a reduction in IA increases the firing rate. Application of 2-AG reduced the peak amplitude of IA and caused faster inactivation. The modulation of IA by 2-AG is likely to underlie the increase in dopamine neuron firing rate, an effect mimicked by pharmacological reduction of IA.
In the brain, endocannabinoids such as 2-AG influence neurons mainly by acting on the cannabinoid receptor 1 (CB1) and CB2. Midbrain dopamine neurons express CB2s, but, interestingly, both the 2-AG-mediated decrease in IA peak amplitude and accelerated inactivation kinetics were not affected by blockade of CBs. This suggests that 2-AG acts via a CB-independent mechanism.
A direct action of 2-AG on Kv4.3 channels was supported by effects of bovine serum albumin (BSA) added to the external saline. BSA, which sequesters 2-AG and related fatty acids from the plasma membrane, rapidly reversed the effects of 2-AG.
2-AG interacts directly with IA channels
In dopamine neurons, activation of metabotropic glutamate receptors (mGluRs), orexin receptors or neurotensin receptors results in increased activation of phospholipase C (PLC), which in turn results in the release of 2-AG. Artificially stimulating each of these three receptors inhibited IA. This effect was unaffected by blockade of CBs but was blocked by inclusion of BSA in the external saline, implying that 2-AG interacts directly with IA channels.
Blocking endogenous 2-AG synthesis or blocking PLC production prevented the inhibition of IA following stimulation of mGluR, orexin receptors or neurotensin receptors, but this could be rescued by application of exogenous 2-AG. Overall, these data suggest that, in mouse midbrain dopamine neurons, tonic and evoked activity can be modulated by a direct interaction between the IA and the lipid mediator 2-AG, which is produced following activation of mGluR, orexin receptors and neurotensin receptors.
Gantz, S. C. & Bean B. P. Cell-autonomous excitation of midbrain dopamine neurons by endocannabinoid-dependent lipid signaling. Neuron http://dx.doi.org/10.1016/j.neuron.2017.02.025 (2017)
About this article
Cite this article
Lewis, S. Changing the (potassium) channel?. Nat Rev Neurosci 18, 266 (2017). https://doi.org/10.1038/nrn.2017.41