TY - JOUR T1 - Role for Endogenous BDNF in Endocannabinoid-mediated Long-Term Depression at Neocortical Inhibitory Synapses JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0029-14.2015 SP - ENEURO.0029-14.2015 AU - Liangfang Zhao AU - Mason Li-Wen Yeh AU - Eric S. Levine Y1 - 2015/03/24 UR - http://www.eneuro.org/content/early/2015/03/24/ENEURO.0029-14.2015.abstract N2 - 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 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. Significance Statement: Endocannabinoids and neurotrophins, particularly brain-derived neurotrophic factor (BDNF), are potent neuromodulators that play critical roles in many behavioral and physiological processes. Disruption of either BDNF or endocannabinoid signaling is associated with an overlapping set of neurologic and psychiatric diseases, and both systems are currently major targets for the development of novel therapeutics, particularly in relation to depression, anxiety, autism, and schizophrenia. Little is known, however, about the interactions between these systems. In the present studies, we find that endogenous BDNF is released in an activity-dependent manner to trigger endocannabinoid-mediated depression of inhibitory synapses. A mechanistic understanding of BDNF-endocannabinoid interactions regulating synaptic plasticity may provide clues to underlying pathologies of neurologic and psychiatric disorders and suggest novel strategies for therapeutic intervention. ER -