NEUROBIOLOGY Endocannabinoids Are Autoinhibiting

Bacci et al. investigated the mechanism by which low-threshold-spiking (LTS) interneurons, which contribute to control of pyramidal cell activity, become inhibited after sustained stimulation (mediated by multiple trains of evoked action potentials triggered by electrophysiology methods). LTS interneurons are inhibitory and they release the neurotransmitter -aminobutyric acid (GABAergic). Because they lack autaptic GABAergic transmission (they do not respond themselves to GABA), another mechanism must exist to mediate inhibitory autoinhibition. Sustained activation of LTS interneurons resulted in long-lasting increases in membrane conductance mediated by activation of a K⁺ channel. The self-inhibition was blocked by the calcium chelator BAPTA, which indicated that elevations in intracellular calcium are involved. Involvement of the endocannabinoid receptor CB1, which is expressed on LTS interneurons and which stimulates the K⁺ channel GIRK (G protein-activated inwardly rectifying K⁺ channel), was confirmed by loss of self-inhibition in the presence of the CB1 antagonist AM251. Furthermore, application of 2-arachidonylglycerol, a cannabinoid, produced hyperpolarization. Thus, endocannabinoids appear to be a mediator of autoinhibition in a subset of interneurons, and a similar mechanism may be responsible for a long-term inhibition of GABAergic signaling observed in the hippocampus and in depolarization-induced inhibition of cerebellar interneurons.

A. Bacci, J. R. Huguenard, D. A. Prince, Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids. Nature 431, 312-316 (2004). [Online Journal]

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