BDNF Evokes Release of Endogenous Cannabinoids at Layer 2/3 Inhibitory Synapses in the Neocortex

Abstract

. The neurotrophin brain-derived neurotrophic factor (BDNF) is a potent regulator of inhibitory synaptic transmission, although the locus of this effect and the underlying mechanisms are controversial. We explored a potential interaction between BDNF and endogenous cannabinoid (endocannabinoid) signaling because activation of type 1 cannabinoid (CB1) receptors potently regulates ␥-aminobutyric acid (GABA) release and both trkB tyrosine kinase receptors and CB1 receptors are highly expressed at synapses in neocortical layer 2/3. Here, we found that the effects of BDNF at inhibitory cortical synapses are mediated by the release of endocannabinoids acting retrogradely at presynaptic CB1 receptors. Specifically, acute application of BDNF rapidly reduced the amplitude of inhibitory postsynaptic currents (IPSCs) via postsynaptic trkB receptor activation because intracellular delivery of the tyrosine kinase inhibitor K252a completely blocked the BDNF effect. Although triggered by postsynaptic trkB activation, BDNF exposure decreased presynaptic release probability, as evidenced by increases in the paired-pulse ratio and coefficient of variation of evoked responses. In addition, BDNF decreased the frequency but not the amplitude of action potential-independent miniature IPSCs and BDNF did not alter the postsynaptic response to locally applied GABA. These results suggest that BDNF induces the release of a retrograde messenger from the postsynaptic cell that regulates presynaptic neurotransmitter release. Consistent with a role for endocannabinoids as the retrograde signal, the effect of BDNF on IPSCs was blocked by CB1 receptor antagonists and was occluded by a cannabinoid receptor agonist. Furthermore, inhibiting endocannabinoid synthesis or transport also disrupted the BDNF effect, implicating postsynaptic endocannabinoid release triggered by BDNF.

Examining FKBP5 mRNA expression in human iPSC-derived neural cells

“…Whole cell patch-clamp electrophysiology was performed on 48 neurons derived from one subject using previously described techniques (Lemtiri-Chlieh et al, 2010). Eight-week old neurons were selected for recording based on morphology, including pyramidal-shaped soma and presence of neurites.…”

Cannabinoid modulation of drug reward and the implications of marijuana legalization

“…The best understood synaptic signals driving eCB mobilization include:, (1) elevated intracellular [Ca 2+ ], (2) G q/11 -coupled receptor (e.g., group I metabotropic glutamate receptors; mGluR1 and mGluR5) binding, or (3) both [Ca 2+ ] and G q/11 receptors acting synergistically (Kano et al, 2009). Additional signals capable of driving eCB synthesis and release include an mGluR1-mediated activation of the adenylyl cyclase-protein kinase A pathway (Azad et al, 2004) and binding of the tyrosine kinase TrkB (Lemtiri-Chlieh, and Levine 2010) or insulin (Labouebe et al, 2013) receptors. eCBs act at presynaptic G i/o -coupled CB 1 receptors to inhibit presynaptic neurotransmitter release (Wilson and Nicoll, 2001; Ohno-Shosaku et al, 2001; Kreitzer and Regehr, 2001; Maejima et al, 2001).…”

Long-term plasticity at inhibitory synapses

“…For example, acute application of BDNF, depending on brain structure, cell type, and developmental status of the brain, can suppress GABA release [27-28] possibly via eCB mobilization [29], or modulate GABAergic transmission in a postsynaptic manner [27,30-33]. An additional level of complexity results from the fact that BDNF can also increase the number of GABAergic terminals [34-36] and regulate the expression of the chloride transporter KCC2 (see below) [37-39].…”