BDNF-induced endocannabinoid release modulates neocortical glutamatergic neurotransmission.
Endocannabinoids (eCBs) and neurotrophins, particularly brain-derived neurotrophic factor (BDNF), are potent neuromodulators found throughout the mammalian neocortex. Both eCBs and BDNF play critical roles in many behavioral and neurophysiological processes and are targets for the development of novel therapeutics. The effects of eCBs and BDNF are primarily mediated by the type 1 cannabinoid (CB1) receptor and the trkB tyrosine kinase receptor, respectively. Our laboratory and others have previously established that BDNF potentiates excitatory transmission by enhancing presynaptic glutamate release and modulating NMDA receptors. In contrast, we have shown that BDNF attenuates inhibitory transmission by inducing postsynaptic release of eCBs that act retrogradely to suppress GABA release in layer 2/3 of somatosensory cortex. Here, we hypothesized that BDNF also induces release of eCBs at excitatory synapses, which could have a mitigating or opposing effect on the direct presynaptic effects of BDNF. We found the highest levels of expression of CB1 and trkB and receptors in layers 2/3 and 5. Surprisingly, BDNF did not increase the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs) onto layer 5 pyramidal neurons in somatosensory cortex, in contrast to its effects in the hippocampus and visual cortex. However, the effect of BDNF on mEPSC frequency in somatosensory cortex was unmasked by blocking CB1 receptors or disrupting eCB release. Thus, BDNF-trKB signaling regulates glutamate release in the somatosensory cortex via opposing effects, a direct presynaptic enhancement of release probability, and simultaneous postsynaptically-induced eCB release that decreases release probability via presynaptic CB1 receptors.
Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave, Farmington, CT, 06030.
Mason L
ML
Yeh
Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave, Farmington, CT, 06030.
Rajamani
R
Selvam
Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave, Farmington, CT, 06030.
Eric S
0000-0002-2535-9509
ES
Levine
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002478:Cells, Cultured; D063388:Endocannabinoids / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055369:Miniature Postsynaptic Potentials; D019579:Neocortex / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D017966:Pyramidal Cells / Q000378:metabolism* / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D013003:Somatosensory Cortex / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D013569:Synapses / Q000378:metabolism / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D063388:Endocannabinoids; D043884:Receptor, Cannabinoid, CB1; D018698:Glutamic Acid; D020813:Receptor, trkB
endocannabinoids; glutamatergic; neocortex; neuromodulators; neurotrophins