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01-05-2016 | Original Article

Cannabinoid receptor-interacting protein Crip1a modulates CB1 receptor signaling in mouse hippocampus

Authors: Stephan Guggenhuber, Alan Alpar, Rongqing Chen, Nina Schmitz, Melanie Wickert, Tobias Mattheus, Anne E. Harasta, Martin Purrio, Nadine Kaiser, Maurice R. Elphick, Krisztina Monory, Werner Kilb, Heiko J. Luhmann, Tibor Harkany, Beat Lutz, Matthias Klugmann

Published in: Brain Structure and Function | Issue 4/2016

Abstract

The cannabinoid type 1 receptor (Cnr1, CB1R) mediates a plethora of physiological functions in the central nervous system as a presynaptic modulator of neurotransmitter release. The recently identified cannabinoid receptor-interacting protein 1a (Cnrip1a, CRIP1a) binds to the C-terminal domain of CB1R, a region known to be important for receptor desensitization and internalization. Evidence that CRIP1a and CB1R interact in vivo has been reported, but the neuroanatomical distribution of CRIP1a is unknown. Moreover, while alterations of hippocampal CRIP1a levels following limbic seizures indicate a role in controlling excessive neuronal activity, the physiological function of CRIP1a in vivo has not been investigated. In this study, we analyzed the spatial distribution of CRIP1a in the hippocampus and examined CRIP1a as a potential modulator of CB1R signaling. We found that Cnrip1a mRNA is co-expressed with Cnr1 mRNA in pyramidal neurons and interneurons of the hippocampal formation. CRIP1a protein profiles were largely segregated from CB1R profiles in mossy cell terminals but not in hippocampal CA1 region. CB1R activation induced relocalization to close proximity with CRIP1a. Adeno-associated virus-mediated overexpression of CRIP1a specifically in the hippocampus revealed that CRIP1a modulates CB1R activity by enhancing cannabinoid-induced G protein activation. CRIP1a overexpression extended the depression of excitatory currents by cannabinoids in pyramidal neurons of the hippocampus and diminished the severity of chemically induced acute epileptiform seizures. Collectively, our data indicate that CRIP1a enhances hippocampal CB1R signaling in vivo.

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Ben-Ari Y, Cossart R (2000) Kainate, a double agent that generates seizures: two decades of progress. Trends Neurosci 23(11):580–587CrossRefPubMed

Blume LC, Bass CE, Childers SR, Dalton GD, Roberts DC, Richardson JM, Xiao R, Selley DE, Howlett AC (2013) Striatal CB1 and D2 receptors regulate expression of each other, CRIP1A and delta opioid systems. J Neurochem 124(6):808–820. doi:10.1111/jnc.12139 CrossRefPubMed

Bojnik E, Turunc E, Armagan G, Kanit L, Benyhe S, Yalcin A, Borsodi A (2012) Changes in the cannabinoid (CB1) receptor expression level and G-protein activation in kainic acid induced seizures. Epilepsy Res 99(1–2):64–68. doi:10.1016/j.eplepsyres.2011.10.020 CrossRefPubMed

Daigle TL, Kwok ML, Mackie K (2008) Regulation of CB1 cannabinoid receptor internalization by a promiscuous phosphorylation-dependent mechanism. J Neurochem 106(1):70–82. doi:10.1111/j.1471-4159.2008.05336.x CrossRefPubMedPubMedCentral

During MJ, Young D, Baer K, Lawlor P, Klugmann M (2003) Development and optimization of adeno-associated virus vector transfer into the central nervous system. Methods Mol Med 76:221–236PubMed

Guggenhuber S, Monory K, Lutz B, Klugmann M (2010) AAV vector-mediated overexpression of CB1 cannabinoid receptor in pyramidal neurons of the hippocampus protects against seizure-induced excitoxicity. PLoS ONE 5(12):e15707. doi:10.1371/journal.pone.0015707 CrossRefPubMedPubMedCentral

Howlett AC, Blume LC, Dalton GD (2010) CB1 cannabinoid receptors and their associated proteins. Curr Med Chem 17(14):1382–1393CrossRefPubMedPubMedCentral

Jin W, Brown S, Roche JP, Hsieh C, Celver JP, Kovoor A, Chavkin C, Mackie K (1999) Distinct domains of the CB1 cannabinoid receptor mediate desensitization and internalization. J Neurosci 19(10):3773–3780PubMed

Kaneko T, Fujiyama F, Hioki H (2002) Immunohistochemical localization of candidates for vesicular glutamate transporters in the rat brain. J Comp Neurol 444(1):39–62CrossRefPubMed

Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M (2009) Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89(1):309–380. doi:10.1152/physrev.00019.2008 CrossRefPubMed

Katona I, Freund TF (2012) Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci 35:529–558. doi:10.1146/annurev-neuro-062111-150420 CrossRefPubMedPubMedCentral

Kawamura Y, Fukaya M, Maejima T, Yoshida T, Miura E, Watanabe M, Ohno-Shosaku T, Kano M (2006) The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J Neurosci 26(11):2991–3001. doi:10.1523/JNEUROSCI.4872-05.2006 CrossRefPubMed

Keimpema E, Barabas K, Morozov YM, Tortoriello G, Torii M, Cameron G, Yanagawa Y, Watanabe M, Mackie K, Harkany T (2010) Differential subcellular recruitment of monoacylglycerol lipase generates spatial specificity of 2-arachidonoyl glycerol signaling during axonal pathfinding. J Neurosci 30(42):13992–14007. doi:10.1523/JNEUROSCI.2126-10.2010 CrossRefPubMedPubMedCentral

Kouznetsova M, Kelley B, Shen M, Thayer SA (2002) Desensitization of cannabinoid-mediated presynaptic inhibition of neurotransmission between rat hippocampal neurons in culture. Mol Pharmacol 61(3):477–485CrossRefPubMed

Lourenco J, Matias I, Marsicano G, Mulle C (2011) Pharmacological activation of kainate receptors drives endocannabinoid mobilization. J Neurosci 31(9):3243–3248. doi:10.1523/JNEUROSCI.3512-10.2011 CrossRefPubMed

Ludanyi A, Eross L, Czirjak S, Vajda J, Halasz P, Watanabe M, Palkovits M, Magloczky Z, Freund TF, Katona I (2008) Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus. J Neurosci 28(12):2976–2990. doi:10.1523/JNEUROSCI.4465-07.2008 CrossRefPubMed

Lutz B (2009) Endocannabinoid signals in the control of emotion. Curr Opin Pharmacol 9(1):46–52. doi:10.1016/j.coph.2008.12.001 CrossRefPubMed

Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11(12):4213–4225CrossRefPubMed

Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutierrez SO, van der Stelt M, Lopez-Rodriguez ML, Casanova E, Schutz G, Zieglgansberger W, Di Marzo V, Behl C, Lutz B (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302(5642):84–88. doi:10.1126/science.1088208 CrossRefPubMed

Massa F, Mancini G, Schmidt H, Steindel F, Mackie K, Angioni C, Oliet SH, Geisslinger G, Lutz B (2010) Alterations in the hippocampal endocannabinoid system in diet-induced obese mice. J Neurosci 30(18):6273–6281. doi:10.1523/JNEUROSCI.2648-09.2010 CrossRefPubMedPubMedCentral

Mechoulam R, Parker LA (2013) The endocannabinoid system and the brain. Annu Rev Psychol 64:21–47. doi:10.1146/annurev-psych-113011-143739 CrossRefPubMed

Mikasova L, Groc L, Choquet D, Manzoni OJ (2008) Altered surface trafficking of presynaptic cannabinoid type 1 receptor in and out synaptic terminals parallels receptor desensitization. Proc Natl Acad Sci USA 105(47):18596–18601. doi:10.1073/pnas.0805959105 CrossRefPubMedPubMedCentral

Monory K, Massa F, Egertova M, Eder M, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M, Long J, Rubenstein JL, Goebbels S, Nave KA, During M, Klugmann M, Wolfel B, Dodt HU, Zieglgansberger W, Wotjak CT, Mackie K, Elphick MR, Marsicano G, Lutz B (2006) The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51(4):455–466. doi:10.1016/j.neuron.2006.07.006 CrossRefPubMedPubMedCentral

Niehaus JL, Liu Y, Wallis KT, Egertova M, Bhartur SG, Mukhopadhyay S, Shi S, He H, Selley DE, Howlett AC, Elphick MR, Lewis DL (2007) CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor interacting protein CRIP 1a. Mol Pharmacol 72(6):1557–1566. doi:10.1124/mol.107.039263 CrossRefPubMed

Ohno-Shosaku T, Tsubokawa H, Mizushima I, Yoneda N, Zimmer A, Kano M (2002) Presynaptic cannabinoid sensitivity is a major determinant of depolarization-induced retrograde suppression at hippocampal synapses. J Neurosci 22(10):3864–3872PubMed

Pertwee RG (2012) Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci 367(1607):3353–3363. doi:10.1098/rstb.2011.0381 CrossRefPubMedPubMedCentral

Ritter SL, Hall RA (2009) Fine-tuning of GPCR activity by receptor-interacting proteins. Nat Rev Mol Cell Biol 10(12):819–830. doi:10.1038/nrm2803 CrossRefPubMedPubMedCentral

Schnell SA, Staines WA, Wessendorf MW (1999) Reduction of lipofuscin-like autofluorescence in fluorescently labeled tissue. J Histochem Cytochem 47(6):719–730CrossRefPubMed

Smith TH, Sim-Selley LJ, Selley DE (2010) Cannabinoid CB1 receptor-interacting proteins: novel targets for central nervous system drug discovery? Br J Pharmacol 160(3):454–466. doi:10.1111/j.1476-5381.2010.00777.x CrossRefPubMedPubMedCentral

Smith TH, Blume LC, Straiker A, Cox JO, David BG, McVoy JS, Sayers KW, Poklis JL, Abdullah RA, Egertova M, Chen CK, Mackie K, Elphick MR, Howlett AC, Selley DE (2015) Cannabinoid receptor interacting protein 1a (CRIP1a) modulates CB1 receptor signaling and regulation. Mol Pharmacol. doi:10.1124/mol.114.096495

Steindel F, Lerner R, Haring M, Ruehle S, Marsicano G, Lutz B, Monory K (2013) Neuron-type specific cannabinoid-mediated G protein signalling in mouse hippocampus. J Neurochem 124(6):795–807. doi:10.1111/jnc.12137 CrossRefPubMed

Straiker A, Wager-Miller J, Mackie K (2012) The CB1 cannabinoid receptor C-terminus regulates receptor desensitization in autaptic hippocampal neurones. Br J Pharmacol 165(8):2652–2659. doi:10.1111/j.1476-5381.2011.01743.x CrossRefPubMedPubMedCentral

von Jonquieres G, Mersmann N, Klugmann CB, Harasta AE, Lutz B, Teahan O, Housley GD, Frohlich D, Kramer-Albers EM, Klugmann M (2013) Glial promoter selectivity following AAV-delivery to the immature brain. PLoS ONE 8(6):e65646. doi:10.1371/journal.pone.0065646 CrossRef

Yoshida T, Fukaya M, Uchigashima M, Miura E, Kamiya H, Kano M, Watanabe M (2006) Localization of diacylglycerol lipase-alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor. J Neurosci 26(18):4740–4751. doi:10.1523/JNEUROSCI.0054-06.2006 CrossRefPubMed

Title: Cannabinoid receptor-interacting protein Crip1a modulates CB1 receptor signaling in mouse hippocampus
Authors: Stephan Guggenhuber
Alan Alpar
Rongqing Chen
Nina Schmitz
Melanie Wickert
Tobias Mattheus
Anne E. Harasta
Martin Purrio
Nadine Kaiser
Maurice R. Elphick
Krisztina Monory
Werner Kilb
Heiko J. Luhmann
Tibor Harkany
Beat Lutz
Matthias Klugmann
Publication date: 01-05-2016
Publisher: Springer Berlin Heidelberg
Published in: Brain Structure and Function / Issue 4/2016
Print ISSN: 1863-2653
Electronic ISSN: 1863-2661
DOI: https://doi.org/10.1007/s00429-015-1027-6

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Cannabinoid receptor-interacting protein Crip1a modulates CB1 receptor signaling in mouse hippocampus

Abstract

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Abstract

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