Endogenous cannabinoids mediate the effect of BDNF at CA1 inhibitory synapses in the hippocampus

Abstract

Brain‐derived neurotrophic factor (BDNF), traditionally known for promoting neuronal growth and development, is also a modulator of synaptic transmission. In addition to the well‐characterized effects at excitatory synapses, BDNF has been shown to acutely suppress inhibitory neurotransmission; however, the underlying mechanisms are unclear. We have previously shown that at inhibitory synapses in layer 2/3 of the somatosensory cortex, BDNF induces the mobilization of endogenous cannabinoids (eCBs) that act retrogradely to suppress GABA release. Here, we hypothesized that in the hippocampus, BDNF acts similarly via eCB signaling to suppress GABAergic transmission. We found that the acute application of BDNF reduced the spontaneous inhibitory postsynaptic currents (sIPSCs) via postsynaptic TrkB receptor activation. The suppressive effects of BDNF required eCB signaling, as this effect on sIPSCs was prevented by a CB1 receptor antagonist. Further, blocking the postsynaptic eCB release prevented the effect of BDNF, whereas eCB reuptake inhibition enhanced the effect of BDNF. These results suggest that BDNF triggers the postsynaptic release of eCBs. To identify the specific eCB release by BDNF, we tested the effects of disrupting the synthesis or degradation of 2‐arachidonoylcglycerol (2‐AG). Blocking 2‐AG synthesis prevented the effect of BDNF and blocking 2‐AG degradation enhanced the effect of BDNF. However, there was no change in the effect of BDNF when anandamide degradation was blocked. Collectively, these results suggest that in the hippocampus, BDNF‐TrkB signaling induces the postsynaptic release of the endogenous cannabinoid 2‐AG, which acts retrogradely on the presynaptic CB1 receptors to suppress GABA release.

A Systematic Review of the Effects of Perinatal Alcohol Exposure and Perinatal Marijuana Exposure on Adult Neurogenesis in the Dentate Gyrus

“…Specifically, alcohol appears to primarily target postsynaptic GABA receptors, whereas cannabinoids seem to target presynaptic CB1 receptors (Kawamura et al, 2006; Sheng and Kim, 2011). Studies done on these receptors in the absence of SAM conditions also support this finding (Chevaleyre and Castillo, 2004; Huang, Lo and Hsu, 2001; Losonczy, Biro and Nusser, 2004; Selvam, Yeh and Levine, 2019).…”

The Changing Brain

“…In pyramidal cells in layers two/three of the somatosensory cortex, BDNF/TrkB signalling induces postsynaptic eCB release via downstream PLCγ signalling (Yeh, Selvam, & Levine, 2017;Lemtiri-Chlieh & Levine, 2010). Similarly, BDNF/TrkB signalling induces postsynaptic 2-AG release within hippocampal cells (Selvam, Yeh, & Levine, 2019). Both of the aforementioned processes were observed at inhibitory synapses.…”

“…At inhibitory GABAergic neurons in the somatosensory cortex, BDNF signalling induces eCB retrograde suppression of GABA release (Yeh et al, 2017). Likewise, in hippocampal GABAergic neurons, BDNF/TrkB signalling induces 2-AG retrograde suppression of GABA release (Selvam et al, 2019).…”

Targeting 2‐arachidonoylglycerol signalling in the neurobiology and treatment of depression

“…The authors also showed that treatment restored the baseline excitability and long‐term potentiation (LTP) impaired by stress, showing that the MAGL inhibitor may modify the neuroplasticity in the ventral hippocampal‐nucleus accumbens pathway 32 . Recently, Selvam et al 40 evidenced that in an inhibitory synapse, the activation of the tropomyosin receptor kinase B (TrkB) by BDNF increased the synthesis of 2‐AG. In a retrograde way, 2‐AG acts in CB1 receptors in the presynaptic neuron, suppressing GABA release, consequently reducing the spontaneous inhibitory postsynaptic currents (sIPSCs) in the hippocampus 40 .…”