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• W1892287994 endingPage "10057" @default.
• W1892287994 startingPage "10039" @default.
• W1892287994 abstract "Persistent CB₁ cannabinoid receptor activity limits neurotransmitter release at various synapses throughout the brain. However, it is not fully understood how constitutively active CB₁ receptors, tonic endocannabinoid signaling, and its regulation by multiple serine hydrolases contribute to the synapse-specific calibration of neurotransmitter release probability. To address this question at perisomatic and dendritic GABAergic synapses in the mouse hippocampus, we used a combination of paired whole-cell patch-clamp recording, liquid chromatography/tandem mass spectrometry, stochastic optical reconstruction microscopy super-resolution imaging, and immunogold electron microscopy. Unexpectedly, application of the CB₁ antagonist and inverse agonist AM251 [<i>N</i>-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-<i>N</i>-1-piperidinyl-1<i>H</i>-pyrazole-3-carboxamide], but not the neutral antagonist NESS0327 [8-chloro-1-(2,4-dichlorophenyl)-<i>N</i>-piperidin-1-yl-5,6-dihydro-4<i>H</i>-benzo[2,3]cyclohepta[2,4-b]pyrazole-3-carboxamine], significantly increased synaptic transmission between CB₁-positive perisomatic interneurons and CA1 pyramidal neurons. JZL184 (4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate), a selective inhibitor of monoacylglycerol lipase (MGL), the presynaptic degrading enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), elicited a robust increase in 2-AG levels and concomitantly decreased GABAergic transmission. In contrast, inhibition of fatty acid amide hydrolase (FAAH) by PF3845 (<i>N</i>-pyridin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide) elevated endocannabinoid/endovanilloid anandamide levels but did not change GABAergic synaptic activity. However, FAAH inhibitors attenuated tonic 2-AG increase and also decreased its synaptic effects. This antagonistic interaction required the activation of the transient receptor potential vanilloid receptor TRPV1, which was concentrated on postsynaptic intracellular membrane cisternae at perisomatic GABAergic symmetrical synapses. Interestingly, neither AM251, JZL184, nor PF3845 affected CB₁-positive dendritic interneuron synapses. Together, these findings are consistent with the possibility that constitutively active CB₁ receptors substantially influence perisomatic GABA release probability and indicate that the synaptic effects of tonic 2-AG release are tightly controlled by presynaptic MGL activity and also by postsynaptic endovanilloid signaling and FAAH activity. <b>SIGNIFICANCE STATEMENT</b> 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." @default.
• W1892287994 created "2016-06-24" @default.
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• W1892287994 date "2015-07-08" @default.
• W1892287994 modified "2023-09-27" @default.
• W1892287994 title "Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release" @default.
• W1892287994 cites W1485038464 @default.
• W1892287994 cites W1488329806 @default.
• W1892287994 cites W1533581117 @default.
• W1892287994 cites W1556695894 @default.
• W1892287994 cites W1591647183 @default.
• W1892287994 cites W1592286181 @default.
• W1892287994 cites W1846159986 @default.
• W1892287994 cites W1949541784 @default.
• W1892287994 cites W1966101832 @default.
• W1892287994 cites W1969338731 @default.
• W1892287994 cites W1969953780 @default.
• W1892287994 cites W1971697848 @default.
• W1892287994 cites W1971951378 @default.
• W1892287994 cites W1974989255 @default.
• W1892287994 cites W1975152710 @default.
• W1892287994 cites W1976835308 @default.
• W1892287994 cites W1978050714 @default.
• W1892287994 cites W1979518536 @default.
• W1892287994 cites W1980787499 @default.
• W1892287994 cites W1980988460 @default.
• W1892287994 cites W1986435336 @default.
• W1892287994 cites W1987685578 @default.
• W1892287994 cites W1987996838 @default.
• W1892287994 cites W1988436577 @default.
• W1892287994 cites W1988834416 @default.
• W1892287994 cites W1991132716 @default.
• W1892287994 cites W1992858116 @default.
• W1892287994 cites W1994532676 @default.
• W1892287994 cites W1996444783 @default.
• W1892287994 cites W2002355116 @default.
• W1892287994 cites W2003159048 @default.
• W1892287994 cites W2004981165 @default.
• W1892287994 cites W2005686453 @default.
• W1892287994 cites W2006295679 @default.
• W1892287994 cites W2006372979 @default.
• W1892287994 cites W2008027377 @default.
• W1892287994 cites W2008565294 @default.
• W1892287994 cites W2009849655 @default.
• W1892287994 cites W2010864051 @default.
• W1892287994 cites W2015923748 @default.
• W1892287994 cites W2020002997 @default.
• W1892287994 cites W2021213638 @default.
• W1892287994 cites W2024356032 @default.
• W1892287994 cites W2025490193 @default.
• W1892287994 cites W2029393114 @default.
• W1892287994 cites W2029418391 @default.
• W1892287994 cites W2030135878 @default.
• W1892287994 cites W2030876219 @default.
• W1892287994 cites W2033044289 @default.
• W1892287994 cites W2041300659 @default.
• W1892287994 cites W2042320851 @default.
• W1892287994 cites W2042587343 @default.
• W1892287994 cites W2043866703 @default.
• W1892287994 cites W2044882055 @default.
• W1892287994 cites W2046099157 @default.
• W1892287994 cites W2050316608 @default.
• W1892287994 cites W2050519455 @default.
• W1892287994 cites W2051554315 @default.
• W1892287994 cites W2052107994 @default.
• W1892287994 cites W2052329951 @default.
• W1892287994 cites W2053029537 @default.
• W1892287994 cites W2053137629 @default.
• W1892287994 cites W2053338618 @default.
• W1892287994 cites W2053703019 @default.
• W1892287994 cites W2054914622 @default.
• W1892287994 cites W2055705346 @default.
• W1892287994 cites W2059254350 @default.
• W1892287994 cites W2062417095 @default.
• W1892287994 cites W2069164397 @default.
• W1892287994 cites W2070581367 @default.
• W1892287994 cites W2076970302 @default.
• W1892287994 cites W2085298050 @default.
• W1892287994 cites W2085300294 @default.
• W1892287994 cites W2088894125 @default.
• W1892287994 cites W2089362566 @default.
• W1892287994 cites W2091980908 @default.
• W1892287994 cites W2091992063 @default.

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