Endocannabinoids control the induction of cerebellar LTD.
The long-term depression (LTD) of parallel fiber (PF) synapses onto Purkinje cells plays a central role in motor learning. Endocannabinoid release and LTD induction both depend upon activation of the metabotropic glutamate receptor mGluR1, require postsynaptic calcium increases, are synapse specific, and have a similar dependence on the associative activation of PF and climbing fiber synapses. These similarities suggest that endocannabinoid release could account for many features of cerebellar LTD. Here we show that LTD induction is blocked by a cannabinoid receptor (CB1R) antagonist, by inhibiting the synthesis of the endocannabinoid 2-arachidonyl glycerol (2-AG), and is absent in mice lacking the CB1R. Although CB1Rs are prominently expressed presynaptically at PF synapses, LTD is expressed postsynaptically. In contrast, a previously described transient form of inhibition mediated by endocannabinoids is expressed presynaptically. This indicates that Purkinje cells release 2-AG that activates CB1Rs to both transiently inhibit release and induce a postsynaptic form of LTD.
Safo
Patrick K
PK
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Regehr
Wade G
WG
D000818:Animals; D001095:Arachidonic Acids / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D002531:Cerebellum / Q000502:physiology*; D004558:Electric Stimulation; D063388:Endocannabinoids; D005989:Glycerides / Q000502:physiology; D066298:In Vitro Techniques; D008071:Lipoprotein Lipase / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000502:physiology; D011689:Purkinje Cells / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000172:deficiency / Q000502:physiology; D013569:Synapses / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; C469526:Cnr2 protein, rat; D063388:Endocannabinoids; D005989:Glycerides; D043885:Receptor, Cannabinoid, CB2; D005680:gamma-Aminobutyric Acid; C094503:glyceryl 2-arachidonate; D008071:Lipoprotein Lipase