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NMDARs and CB1Rs (Bender et al., 2006; Nevian and Sakmann, 2006; Sjostrom et al., 2003). Surprisingly, a current study located that astrocytic CB1Rs had been needed and enough to mediate tLTD (Min and Nevian, 2012). eCBs originating from layer 2/3 pyramidal neurons activated astrocytic CB1Rs, which elevated intracellular Ca2+, thereby releasing glutamate and stimulating presynaptic NMDARs (Fig. 4B). Provided the anatomical and functional evidence for presynaptic CB1Rs in neocortex (Domenici et al., 2006; Hill et al., 2007; Lafourcade et al., 2007), future studiesNeuron. Author manuscript; readily available in PMC 2013 October 04.SC-43 manufacturer Castillo et al.Pagecould use astrocyte- and neuron-specific CB1R knockout mice to identify the precise conditions needed to activate neuronal and/or astrocytic CB1Rs. Attesting to the attainable physiological relevance of astrocytic CB1Rs, a recent in vivo study showed that intraperitoneal injection of THC induced long-lasting suppression of excitatory synaptic transmission in hippocampal location CA1, an effect that essential astrocytic CB1Rs (Han et al., 2012). Earlier perform in acute hippocampal slices from worldwide CB1R knockout mice suggested that agonist-mediated suppression of excitatory transmission in CA1 depends solely on CB1Rs expressed at Schaffer collateral terminals (Katona et al., 2006; Kawamura et al., 2006; Takahashi and Castillo, 2006). Unexpectedly, nonetheless, THCmediated suppression of synaptic transmission in vivo was intact in glutamatergic and GABAergic distinct CB1R knockout mice, whereas it was abolished in glia-specific CB1R knockout mice (Han et al., 2012). Mechanistically, glutamate, presumably released from astrocytes, activated postsynaptic NMDARs, triggering AMPAR endocytosis and subsequent synaptic depression. These final results contrast with these observed in vitro in which eCBs indirectly facilitated synaptic transmission by way of astrocytic CB1Rs (Navarrete and Araque, 2008, 2010). A thorough examination from the situations important for activating synaptic and astrocytic CB1Rs is clearly required.watermark-text watermark-text watermark-textTonic Endocannabinoid SignalingIn addition towards the classical, activity-dependent phasic mode of eCB mobilization, tonic eCB signaling has been reported. Tonic signaling is usually observed as an increase in basal synaptic transmission following pharmacological blockade of CB1Rs (Auclair et al., 2000; Hentges et al., 2005; Losonczy et al., 2004; Neu et al., 2007; Oliet et al., 2007; Slanina and Schweitzer, 2005; Zhu and Lovinger, 2010). Having said that, CB1R blockade in this manner doesn’t often reveal an eCB tone (Chevaleyre and Castillo, 2003; Pan et al., 2011; van Beugen et al., 2006; Wilson and Nicoll, 2001; Zhong et al., 2011). Build-up of an eCB tone can happen when inhibiting eCB uptake (Wilson and Nicoll, 2001) or genetic deletion of MGL (Pan et al., 2011; Zhong et al., 2011). The fact that most 2-AG is hydrolyzed by MGL (Blankman et al., 2007; Chanda et al., 2010; Nomura et al., 2011) suggests 2-AG mediates tonic eCB signaling, which is consistent having a constitutive release of 2-AG in cultured neurons (Hashimotodani et al., 2007b). Alternatively, AEA can also contribute to tonic eCB signaling. Chronic inactivity in hippocampal slice cultures reduced an AEA tone presumably by augmenting AEA uptake and degradation (Kim and Alger, 2010). With each other, these studies suggest tonic eCB signaling can control, beneath some conditions, basal synaptic neurotransmitter release. It is actually curre.