Retrograde Inhibitor

Abstract

Three groups (Wilson and Nicoll, Ohno-Shosaku et al. , and Kreitzer and Regehr) have reported that cannabinoids mediate a retrograde signal from postsynaptic cells to presynaptic neurons that inhibits the activity of the presynaptic cell. Wilson and Nicoll and Ohno-Shosaku et al. show that in the hippocampus cannabinoid receptor (CB1) agonists produce inhibition of inhibitory synaptic activity because of presynaptic cell activation. These same groups also show that depolarization of the postsynaptic cell causes suppression of presynaptic activity [also known as depolarization-induced suppression of inhibition (DSI)], which requires calcium influx into the postsynaptic cell and is inhibited by CB1 receptor antagonists. Wilson and Nicoll demonstrate that inhibition of the cannabinoid transporter also produces an inhibition of the presynaptic neuron and occludes the formation of DSI (because the presynaptic nerve is already inhibited), confirming the importance of endogenous cannabinoids for this inhibitory activity. Christie and Vaughan provide an overview of this retrograde messenger, primarily in the context of DSI, in an accompanying News and Views article. Kreitzer and Regehr provide evidence for cannabinoids acting as retrograde messengers to inhibit presynaptic activity at excitatory synapses in the cerebellum. They first demonstrate that excitatory synaptic inputs on Purkinje cells from climbing fibers and parallel fibers exhibit depolarization-induced suppression of excitation (DSE) that is dependent on calcium influx in the postsynaptic cell. Furthermore, conditions that produce DSE result in a decrease in calcium influx in the presynaptic cell showing a presynaptic mechanism underlying the inhibition. DSE could be inhibited by CB1 antagonists and was occluded by the preincubation of the cerebellar slice with CB1 agonists, consistent with endogenous cannabinoids mediating the signal from the postsynaptic cell to the presynaptic cell. R. I. Wilson, R. A. Nicoll, Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410 , 588-592 (2001). [Online Journal] T. Ohno-Shosaku, T. Maejima, M. Kano, Endoegenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron 29 , 729-738 (2001). [Online Journal] A. C. Kreitzer, W. G. Regehr, Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29 , 717-727 (2001). [Online Journal] M. J. Christie, C. W. Vaughan, Cannabinoids act backwards. Nature 410 , 527-530 (2001). [Online Journal]