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

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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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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft FOR926 (subprojects SP3 to B. L. and K. M.), SFB 1080 (subprojects A1 to H. J. L. and B8 to B. L.), the Australian Research Council (ARC Future Fellowship to M. K.), the Hungarian Brain Research Program, KTIA_NAP_13-2-2014-0013 (to A.A.), the Swedish Medical Research Council and the Novo Nordisk Foundation (T. H.). We thank Ruth Jelinek for excellent help with vector production; Erik Keimpema and Klaudia Barabas for input at early stages of the manuscript; Ken Mackie and Deborah Lewis for the CRIP1a antibodies and the rat Cnrip1a cDNA.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany

    Stephan Guggenhuber, Nina Schmitz, Melanie Wickert, Tobias Mattheus, Anne E. Harasta, Martin Purrio, Nadine Kaiser, Krisztina Monory, Beat Lutz & Matthias Klugmann

  2. Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 1:A1, 17177, Stockholm, Sweden

    Alan Alpar & Tibor Harkany

  3. Research Group of Experimental Neuroanatomy and Developmental Biology, Hungarian Academy of Sciences, Budapest, Hungary

    Alan Alpar

  4. Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary

    Alan Alpar

  5. Institute of Physiology, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany

    Rongqing Chen, Werner Kilb & Heiko J. Luhmann

  6. Department of Physiology and Translational Neuroscience Facility, School of Medical Sciences, UNSW, High Street, Randwick, Sydney, NSW, 2052, Australia

    Anne E. Harasta & Matthias Klugmann

  7. Department of Molecular Neuroscience, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria

    Tibor Harkany

  8. School of Biological and Chemical Sciences, Queen Mary University of London, London, E1 4NS, UK

    Maurice R. Elphick

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  1. Stephan Guggenhuber
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  5. Melanie Wickert
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  8. Martin Purrio
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  9. Nadine Kaiser
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  10. Maurice R. Elphick
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  15. Beat Lutz
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Correspondence to Beat Lutz or Matthias Klugmann.

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Guggenhuber, S., Alpar, A., Chen, R. et al. Cannabinoid receptor-interacting protein Crip1a modulates CB1 receptor signaling in mouse hippocampus. Brain Struct Funct 221, 2061–2074 (2016). https://doi.org/10.1007/s00429-015-1027-6

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