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Abstract
Tonic cannabinoid signaling plays a critical role in the regulation of synaptic transmission. However, the mechanistic details of how persistent CB1 cannabinoid receptor activity inhibits neurotransmitter release have remained elusive. Therefore, electrophysiological recordings, lipid measurements, and super-resolution imaging were combined to elucidate those signaling molecules and mechanisms that underlie tonic cannabinoid signaling. The findings indicate that constitutive CB1 activity has pivotal function in the tonic control of hippocampal GABA release. Moreover, the endocannabinoid 2-arachidonoylglycerol (2-AG) is continuously generated postsynaptically, but its synaptic effect is regulated strictly by presynaptic monoacylglycerol lipase activity. Finally, anandamide signaling antagonizes tonic 2-AG signaling via activation of postsynaptic transient receptor potential vanilloid TRPV1 receptors. This unexpected mechanistic diversity may be necessary to fine-tune GABA release probability under various physiological and pathophysiological conditions.
Highlights
Neurons set their synaptic strength by using several signaling mechanisms that dynamically adjust parameters of synaptic transmission, including neurotransmitter release probability (Branco and Staras, 2009)
CB1-positive interneurons with the typical regular spiking pattern represent a morphologically heterogeneous population of several distinct GABAergic cell types in the hippocampus, which can be best characterized on the basis of the layer-specific distribution of their axonal arbors (Cope et al, 2002; Pawelzik et al, 2002; Klausberger and Somogyi, 2008; Nissen et al, 2010; Szaboet al., 2014b; Dudok et al, 2015; Lenkey et al, 2015)
Our present findings indicate the following: (1) constitutively active CB1 receptors set GABA release probability selectively at perisomatic synapses in the hippocampus; (2) 2-AG is the primary mediator of ligand-driven tonic endocannabinoid signaling, but it is tightly controlled by presynaptic monoacylglycerol lipase (MGL) activity; (3) a major regulatory mechanism calibrating the homosynaptic 2-AG-mediated endocannabinoid tone is endovanilloid signaling, which requires the activation of TRPV1 channels predominantly located on postsynaptic intracellular stores at GABAergic synapses; and (4) endovanilloid regulation of the 2-AG-mediated tone is controlled by fatty acid amide hydrolase (FAAH)
Summary
Neurons set their synaptic strength by using several signaling mechanisms that dynamically adjust parameters of synaptic transmission, including neurotransmitter release probability (Branco and Staras, 2009). The lipid messengers anandamide and 2-arachidonoylglycerol (2-AG) are both released from postsynaptic neurons and act retrogradely on presynaptic CB1 receptors (Ohno-Shosaku and Kano, 2014) Their synaptic levels are determined by complex enzymatic interactions with numerous synthesis and degradation routes identified in the brain (Blankman and Cravatt, 2013). Because anandamide and 2-AG are known to participate differentially in specific behavioral processes (Long et al, 2009a), it is generally assumed that this molecular and functional complexity reflects division of labor in setting synaptic strength in the underlying brain circuits. It is not clear whether it is 2-AG or anandamide, which primarily contributes to the tonic control of neurotransmitter release at given circuit locations. Emerging in vitro and in vivo observations raised the possibility that constitutive receptor activity may influence axonal CB1 distribution and tonically attenuate GABA release in the forebrain (Leterrier et al, 2006; Meye et al, 2013; Thibault et al, 2013)
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