Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release

The Journal of Neuroscience, July 8, 2015 • 35(27):10039–10057 • 10039 Cellular/Molecular Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release X Sang-Hun Lee,1* Marco Ledri,2* Blanka To´th,3* Ivan Marchionni,1 Christopher M. Henstridge,2 XBarna Dudok,2,4 Kata Kenesei,2 La´szlo´ Barna,2 Szila´rd I. Szabo´,2 Tibor Renkecz,3 XMichelle Oberoi,1 Masahiko Watanabe,5 Charles L. Limoli,7 George Horvai,3,6 Ivan Soltesz,1* and XIstva´n Katona2* 1Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697, 2Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary, 3Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, H-1111 Budapest, Hungary, 4School of PhD Studies, Semmelweis University, H-1769 Budapest, Hungary, 5Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan, 6MTA-BME Research Group of Technical Analytical Chemistry, H-1111 Budapest, Hungary, and 7Department of Radiation Oncology, University of California, Irvine, California 92697 PersistentCB1cannabinoidreceptoractivitylimitsneurotransmitterreleaseatvarioussynapsesthroughoutthebrain.However,itisnotfullyunderstood 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 inverseagonistAM251[N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide],butnottheneutralantag- onist NESS0327 [8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-5,6-dihydro-4H-benzo[2,3]cyclohepta[2,4-b]pyrazole-3-carboxamine], signifi- cantly 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 (N-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. Key words: 2-arachidonoylglycerol; endocannabinod; GABA; hippocampus; interneuron; TRPV1 Significance Statement 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 hippocampalGABArelease.Moreover,theendocannabinoid2-arachidonoylglycerol(2-AG)iscontinuouslygeneratedpostsynaptically, 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. 10040 • J. Neurosci., July 8, 2015 • 35(27):10039–10057 Lee et al. • Tonic Cannabinoid Control of GABAergic Synapses Introduction Because the cannabinoid tone plays a major role in Neurons set their synaptic strength by using several signaling interneuron-type-specific and activity-dependent adjustment of mechanisms that dynamically adjust parameters of synaptic GABAergic synaptic strength, a better understanding of the un- transmission, including neurotransmitter release probability derlying signaling processes is important (Losonczy et al., 2004; (Branco and Staras, 2009). Endocannabinoid signaling is one of Ali and Todorova, 2010; Lee et al., 2010). In addition, recent the most widespread and efficient mechanisms to control release studies have reported selective, long-term pathological altera- tions in the tonic endocannabinoid control of GABA release in probability via presynaptic CB1 cannabinoid receptor activation rodent models of major brain disorders, including autism, Hun- (Lovinger, 2008). Accordingly, CB1 receptors are indispensable for various phasic forms of synaptic plasticity (Castillo et al., tington’s disease, and seizures (Chen et al., 2003, 2007; Dvorzhak 2012) and have an essential function in the tonic control of neu- et al., 2013; Fo¨ldy et al., 2013). Therefore, we used paired patch- rotransmitter release (Losonczy et al., 2004; Hentges et al., 2005; clamp recordings in acute brain slices, in combination with mass Zhu and Lovinger, 2005; Neu et al., 2007; Oliet et al., 2007). spectrometry, stochastic optical reconstruction microscopy However, although the molecular mechanisms accounting for (STORM) super-resolution imaging, and immunogold electron phasic endocannabinoid signaling have been outlined in consid- microscopy, to identify the specific mechanisms that mediate the erable detail previously (Ohno-Shosaku and Kano, 2014), our tonic control of GABA release in the mouse hippocampus. The understanding of how tonic regulation of neurotransmitter re- findings indicate that constitutively active CB1 receptors play a lease is organized and controlled by specific regulatory mecha- considerable role in the regulation of GABA release probability nisms is rather limited. and elucidate a functional interaction between intercellular 2-AG The lipid messengers anandamide and 2-arachidonoylglycerol endocannabinoid and intracellular anandamide endovanilloid (2-AG) are both released from postsynaptic neurons and act retro- signaling in setting the strength of synaptic inhibition. gradely on presynaptic CB1 receptors (Ohno-Shosaku and Kano, 2014). Their synaptic levels are determined by complex enzymatic Materials and Methods interactions with numerous synthesis and degradation routes iden- Animals. All protocols related were approved by the Institutional Animal tified in the brain (Blankman and Cravatt, 2013). Because anand- Care and Use Committee of the University of California, Irvine, and the amide and 2-AG are known to participate differentially in specific Hungarian Committee of the Scientific Ethics of Animal Research (license number XIV-1-001/2332-4/2012), and all animal experiments behavioral processes (Long et al., 2009a), it is generally assumed that were performed according to the Hungarian Act of Animal Care and this molecular and functional complexity reflects division of labor in Experimentation (1998, XXVIII, Section 243/1998), which are in accor- setting synaptic strength in the underlying brain circuits. However, it dance with the European Communities Council Directive of November is not clear whether it is 2-AG or anandamide, which primarily con- 24, 1986 (86/609/EEC; Section 243/1998). All efforts were made to min- tributes to the tonic control of neurotransmitter release at given imize pain and suffering and to reduce the number of animals used. circuit locations. For example, previous studies using culture prep- Adult male C57BL/6 mice aged 4–7 weeks were used in the electrophys- arations and pharmacological tools with limited target selectivity iological, anatomical, and analytical chemistry experiments. In the elec- arrived at different conclusions concerning the identity of the endo- trophysiological experiments testing the role of TRPV1, adult C57BL/6 Ϫ/Ϫ cannabinoid responsible for tonic action at hippocampal GABAer- wild-type and TRPV1 mice of either sex (The Jackson Laboratory) gic synapses (Hashimotodani et al., 2007; Kim and Alger, 2010). aged 4–7 weeks were used. Electrophysiological recordings. The procedures of electrophysiology Moreover, emerging in vitro and in vivo observations raised the pos- experiments are similar to those described previously by Lee et al. (2010). sibility that constitutive receptor

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