Document Type



Medicine and Health Sciences


The endogenous cannabinoid (endocannabinoid) system is an important regulator of synaptic function. Endocannabinoids acutely modulate inhibitory and excitatory transmission, and also mediate long-term depression at GABAergic and glutamatergic synapses. Typically, endocannabinoid synthesis and release is stimulated by depolarization-induced calcium influx and/or activation of phospholipase-C (PLC) signaling triggered by mGluR activation. Recently it has been shown that brain-derived neurotrophic factor (BDNF) can also induce endocannabinoid release. Although there is growing evidence for cross-talk between BDNF and endocannabinoid signaling, little is known about the functional relevance of these interactions. In the present studies, we examined BDNF – endocannabinoid interactions in regulating activity-dependent long-term depression at inhibitory synapses (iLTD). We found that theta burst stimulation (TBS) in layer 2/3 of mouse somatosensory cortical slices can induce a form of endocannabinoid-mediated iLTD that is independent of metabotropic glutamate receptor (mGluR) activation. This endocannabinoid-dependent iLTD, however, requires endogenous BDNF-trkB signaling, as it is blocked by a trk tyrosine kinase inhibitor and by a trkB receptor antagonist, and also requires activation of diacylglycerol lipase (DAG-lipase, DGL). In addition, endocannabinoid-mediated iLTD can be induced by combining a subthreshold concentration of exogenous BDNF with weak TBS stimulation that by itself is insufficient to induce iLTD. Taken together, our results suggest that TBS can induce the release of endogenous BDNF, which triggers DGL-dependent endocannabinoid mobilization and cannabinoid receptor-dependent iLTD at layer 2/3 cortical synapses


Eneuro. Author manuscript; available in PMC 2015 Apr 30. Published in final edited form as: Eneuro. 2015 Feb 28; 2(2): e0029-14.2015. Published online 2015 Mar 24. doi: 10.1523/ENEURO.0029-14.2015 PMCID: PMC4415885 NIHMSID: NIHMS684239