SYNAPTIC PLASTICITY Endocannabinoids: Inhibiting Inhibitory Input

Cannabinoids are active components in marijuana, and endocannabinoids, which are derived from lipids through the actions of such enzymes as phospholipase D, phospholipase A, and diacylglycerol (DAG) lipase, are the body's own version of these signaling molecules. Endocannabinoids were known to mediate a retrograde signal that can transiently regulate inhibitory neurons in the brain. Chevaleyre and Castillo show that endocannabinoids, specifically 2-arachidonyl glycerol (2-AG), mediate a long-term depression (LTD) of inhibitory input (I-LTD) in the hippocampus. I-LTD was produced in response to two types of high-frequency stimulation under conditions where ionotropic glutamate receptors (N-methyl-D-aspartate and the kainate and AMPA receptors) were blocked. This I-LTD only occurred upon stimulation of neurons that synapsed on the dendritic regions of the hippocampal CA1 neurons and not the somatic regions. Pharmacological manipulation indicated that I-LTD required metabotropic glutamate type I receptors (mGluR1), but not -aminobutyric acid B (GABA_B) receptors. Because electrophysiological data suggested that the I-LTD was due to decreased inhibitory input in response to postsynaptic activity, the authors tested for the involvement of a retrograde signal. Pharmacological inhibition of the endocannabinoid receptor CB₁ blocked I-LTD produced through high-frequency stimulation or in response to pharmacological activation of mGluR1. Experiments designed to compare I-LTD with the transient form of inhibition mediated by endocannabinoids suggested that these two events were mediated by different endocannabinoids produced in response to different signaling cascades. The transient form of inhibition requires a calcium-dependent production of endocannabinoids, whereas I-LTD required phospholipase C activation, production of DAG, and the activity of DAG lipase, which produces 2-AG. Further discussion of these two endocannabinoid-mediated inhibitory processes and their roles in long-term potentiation and learning and memory is provided by Freund and Hájos.

V. Chevaleyre, P. E. Castillo, Heterosynaptic LTD of hippocampal GABAergic synapses: A novel role of endocannabinoids in regulating excitability. Neuron 38, 461-472 (2003). [Online Journal]

T. F. Freund, N. Hájos, Excitement reduces inhibition via endocannabinoids. Neuron 38, 362-365 (2003). [Online Journal]