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The Journal of Neuroscience, June 21, 2006, 26(25):6841-6850; doi:10.1523/JNEUROSCI.1280-06.2006

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Cellular/Molecular
Sustained Elevation of Dendritic Calcium Evokes Widespread Endocannabinoid Release and Suppression of Synapses onto Cerebellar Purkinje Cells

Stephan D. Brenowitz, Aaron R. Best, and Wade G. Regehr

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Wade G. Regehr, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. Email: wade_regehr{at}hms.harvard.edu

Endocannabinoids can act as retrograde messengers that allow postsynaptic cells to regulate the strength of their synaptic inputs. In the cerebellum, Purkinje cells (PCs) release endocannabinoids through two mechanisms. Synaptic activation evokes local endocannabinoid release that relies on a pathway that involves the metabotropic glutamate receptor mGluR1 and phospholipase-C (PLC). In contrast, depolarization evokes endocannabinoid release from the entire dendritic arbor. This leads to depolarization-induced suppression of inhibitory (DSI) and excitatory (DSE) synapses by a mechanism that does not involve mGluR1 or PLC. This latter mechanism of endocannabinoid release has only been observed under artificial conditions that transiently elevate postsynaptic calcium to >5 µM. Here, we tested the possibility that this mechanism could lead to retrograde inhibition in response to more realistic calcium signals. At both climbing fiber and inhibitory synapses onto PCs, we found that prolonging the elevation of calcium significantly lowered the peak calcium required to evoke PLC-independent endocannabinoid release. This suggests that the mechanism of endocannabinoid release involved in DSI and DSE is likely to evoke endocannabinoid release in response to physiologically relevant levels of calcium. When dendritic calcium was elevated to 0.4–1 µM for 15 s or more, endocannabinoid release from PCs selectively suppressed inhibitory synapses. This suggests that inhibitory synapses are more sensitive to prolonged calcium increases. Thus, in contrast to localized retrograde inhibition evoked by synaptic activation, modest but sustained calcium elevation could globally suppress inhibitory synapses onto PCs.

Key words: cerebellum; synaptic plasticity; endocannabinoids; calcium; Purkinje cell; two-photon imaging; retrograde inhibition

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Received March 24, 2006; revised May 23, 2006; accepted May 23, 2006.

Correspondence should be addressed to Wade G. Regehr, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. Email: wade_regehr{at}hms.harvard.edu

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