Endocannabinoid Mediates Excitatory Synaptic Function of β-Neurexins. Commentary: β-Neurexins Control Neural Circuits by Regulating Synaptic Endocannabinoid Signaling

摘要

Introduction Synaptic cell-adhesion molecules and their interactions with other molecular pathways affect both synapse formation and its function (Varoqueaux et al., 2006 ; Sudhof, 2008 ; Bemben et al., 2015a ). Neurexins are presynaptic cell-adhesion molecules that interact with neuroligins and other postsynaptic partners. Neurexins are encoded by three genes, each of which encodes a long and short isoform, termed α- and β-neurexins, respectively (Sudhof, 2008 ). Interestingly, despite studies linking neurexins to autism and other neuropsychiatric disorders (Leone et al., 2010 ; Rabaneda et al., 2014 ), the precise cellular mechanisms underlying the role of neurexins in cognition remain poorly understood.Since most biochemical studies of neurexins have focused on β-neurexins, investigating the synaptic actions of β-neurexins is particularly imperative. In their timely Cell article, Anderson et al. reported that β-neurexins selectively modulate synaptic strength at excitatory synapses by regulating postsynaptic endocannabinoid synthesis, describing an unexpected trans-synaptic mechanism for β-neurexins to control neural circuits via endocannabinoid signaling (Anderson et al., 2015 ; Summarized in Figure 1A ). Figure 1 Transsynaptic regulation of endocannabinoid signaling by β-neurexins and its implications in synaptic plasticity and diseases. (A) Regulation of excitatory synaptic strength by β-neurexins via endocannabinoid system. Anderson et al. demonstrated that presynaptic β-neurexins regulate endocannabinoid signaling by controlling postsynaptic endocannabinoid 2-AG synthesis. When β –neurexins are removed, 2-AG synthesis is disinhibited, presynaptic CB1Rs are activated, and synaptic strength is decreased (Anderson et al., 2015 ). In addition, the AC-PKA dependent LTP in burst-firing neurons is blocked, which may account for the impaired contextual memory in hippocampal CA1 β-neurexin knockout mice. β-neurexins act as a brake on endocannabinoid signaling possibly via transsynaptic interaction with postsynaptic neuroligin isoforms that exclusively bind to β-neurexins, but not a-neurexins (Anderson et al., 2015 ). β-neurexins might downregulate tonic endocannabinoid signaling through mGluR1/5 or M1/M3 receptors since activation of those GPCRs is known to trigger 2-AG production via PLC pathway (Varma et al., 2001 ; Chevaleyre et al., 2006 ; Heifets and Castillo, 2009 ; Kano et al., 2009 ; Castillo et al., 2012 ; Rinaldo and Hansel, 2013 ; Martin et al., 2015 ). This regulation might also involve VGCCs, NMDARs, or AMPARs as Ca~(2+)influx through these channels could facilitate PLC-DAGL mediated 2-AG production (Ohno-Shosaku et al., 2005 ; Castillo et al., 2012 ). The exact postsynaptic partners of β-neurexins in this process await to be identified. (B) The regulation of endocannabinoid signaling by β-neurexins supports neurexinseuroligins-endocannabinoid signaling as a common pathomechanism in cognitive disorders (Krueger and Brose, 2013 ; Anderson et al., 2015 ). Abnormalities in this signaling pathway could disrupt synapses and neural circuits, and contribute to neurological and psychiatric diseases (Chubykin et al., 2005 ; Tabuchi et al., 2007 ; Katona and Freund, 2008 ; Sudhof, 2008 ; Gogolla et al., 2009 ; Bot et al., 2011 ; Etherton et al., 2011 ; Foldy et al., 2013 ; Singh and Eroglu, 2013 ; Rothwell et al., 2014 ; Sindi et al., 2014 ; Aoto et al., 2015 ; Bedse et al., 2015 ; Born et al., 2015 ; Di Marzo et al., 2015 ; Parsons and Hurd, 2015 ; Wang and Doering, 2015 ; Wang et al., 2015 ; Bemben et al., 2015b ; Chanda et al., 2016 ). Abbreviations: 2-AG, 2-arachidonoyl-sn-glycerol; AC, adenylyl cyclase; AMPAR, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CB1R, cannabinoid receptor 1; DAG, diacylglycerol; DAGL, diacylglycerol lipase; LTP, long-term potentiation; M1/3R, muscarinic acetylcholine receptor 1/3; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartate receptor; PIP2, phosphatidylinositol 4, 5-bisphosphate; PKA, protein kinase A; PLC, phospholipase C; VGCC, voltage-gated Ca~(2+)channels. β-Neurexins regulate excitatory neurotransmission via endocannabinoid signaling Functional study of neurexins represents a major technical challenge due to their diversity and complexity. To study the specific role of β-neurexins, Anderson et al. generated conditional knockout mice of all β-neurexin genes. Using electrophysiological and pharmacological approaches, the authors elegantly analyzed neurotransmission and synaptic strength in preparations of cultured cortical neurons and acute subiculum slices from those β-neurexin knockout mice (Anderson et al., 2015 ).Can β-neurexins be specifically involved in excitatory or inhibitory neurotransmission? In cultured cortical neurons, Anderson et al. found that β-neurexin knockout decreased the excitatory synapse parameters including AMPA receptor- and NMDA receptor-mediated excitatory postsynaptic currents (EPSCs), release probab