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Stephan D Brenowitz

Publications and source records attributed to Stephan D Brenowitz.

5 recordsLinked to original sources
PubMed2006

Sustained elevation of dendritic calcium evokes widespread endocannabinoid release and suppression of synapses onto cerebellar Purkinje cells.

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 microm. 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 microm 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.

Animals↗
PubMed2005

Associative short-term synaptic plasticity mediated by endocannabinoids.

Associative learning is important on rapid timescales, but no suitable form of short-term plasticity has been identified that is both associative and synapse specific. Here, we assess whether endocannabinoids can mediate such plasticity. In the cerebellum, bursts of parallel fiber (PF) activity evoke endocannabinoid release from Purkinje cell dendrites that results in retrograde synaptic inhibition lasting seconds. We find that the powerful climbing fiber (CF) to Purkinje cell synapse regulates this inhibition. Compared to PF stimulation alone, coactivation of PF and CF synapses greatly enhanced endocannabinoid-mediated inhibition of PF synapses. Retrograde inhibition was restricted to PFs activated within several hundred milliseconds of CF activation. This associative plasticity reflects two aspects of calcium-dependent endocannabinoid release. First, PF-mediated activation of metabotropic glutamate receptors locally reduced the dendritic calcium levels required for endocannabinoid release. Second, CF and PF coactivation evoked localized supralinear dendritic calcium signals. Thus, endocannabinoids mediate transient associative synaptic plasticity.

Action Potentials↗
PubMed2003

Brief presynaptic bursts evoke synapse-specific retrograde inhibition mediated by endogenous cannabinoids.

Many types of neurons can release endocannabinoids that act as retrograde signals to inhibit neurotransmitter release from presynaptic terminals. Little is known, however, about the properties or role of such inhibition under physiological conditions. Here we report that brief bursts of presynaptic activity evoked endocannabinoid release, which strongly inhibited parallel fiber-to-Purkinje cell synapses in rat cerebellar slices. This retrograde inhibition was triggered by activation of either postsynaptic metabotropic or ionotropic glutamate receptors and was restricted to synapses activated with high-frequency bursts. Thus, endocannabinoids allow neurons to inhibit specific synaptic inputs in response to a burst, thereby dynamically fine-tuning the properties of synaptic integration.

Animals↗
PubMed2003

Calcium dependence of retrograde inhibition by endocannabinoids at synapses onto Purkinje cells.

Many types of neurons release endocannabinoids from their dendrites in response to elevation of intracellular calcium levels. Endocannabinoids then activate presynaptic cannabinoid receptors, thereby inhibiting neurotransmitter release for tens of seconds. A crucial step in understanding the physiological role of this retrograde signaling is to determine its sensitivity to elevations of postsynaptic calcium. Here we determine and compare the calcium dependence of endocannabinoid-mediated retrograde inhibition at three types of synapses onto cerebellar Purkinje cells. Previous studies have shown that Purkinje cell depolarization results in endocannabinoid-mediated retrograde inhibition of synapses received from climbing fibers, granule cell parallel fibers, and inhibitory interneurons. Using several calcium indicators with a range of affinities, we performed a series of in situ and in vitro calibrations to quantify calcium levels in Purkinje cells. We found that postsynaptic calcium levels of approximately 15 microM are required for half-maximal retrograde inhibition at all of these synapses. In contrast, previous studies had suggested that endocannabinoid release could occur with slight elevations of calcium above resting levels, which implies that inhibition should be widespread and continuously modulated by subtle changes in intracellular calcium levels. However, our results indicate that such small changes in intracellular calcium are not sufficient to evoke endocannabinoid release. Instead, because of its high requirement for calcium, retrograde inhibition mediated by calcium-dependent endocannabinoid release from Purkinje cells will occur under more restricted conditions and with greater spatial localization than previously appreciated.

Animals↗