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

Abstract

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 ​Figure1A1A). Open in a separate window 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 Ca2+ 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 neurexins/neuroligins-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 Ca2+ channels.