Endocannabinoids serve as retrograde messengers in many brain regions. These diffusible lipophilic molecules are released by postsynaptic cells and regulate presynaptic neurotransmitter release. Here we describe an additional mechanism that mediates the spread of endocannabinoid signaling to distant inhibitory synapses. Depolarization of cerebellar Purkinje cells reduced the firing rate of nearby interneurons, and this reduction in firing was blocked by the cannabinoid receptor antagonist AM251. The cannabinoid receptor agonist WIN55,212-2 also reduced firing rates in interneurons, and this inhibition arose from the activation of a small potassium conductance. Thus, endocannabinoids released from the dendrites of depolarized neurons can lead to inhibition of firing in nearby cells. Because interneurons can project over several hundred micrometers, this inhibition of firing allows cells to regulate synaptic inputs at distances well beyond the limits of endocannabinoid diffusion.
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