Brain Structure and Function

, Volume 221, Issue 4, pp 2061–2074 | Cite as

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

  • 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
Original Article

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.

Keywords

Cannabinoid receptor-interacting protein 1a CRIP1a Hippocampus Cannabinoid receptor CB1R Seizures AAV 

Supplementary material

429_2015_1027_MOESM1_ESM.docx (23 kb)
Supplementary material 1 (DOCX 23 kb)
429_2015_1027_MOESM2_ESM.tif (178 kb)
Supplementary material 2 (TIFF 177 kb)
429_2015_1027_MOESM3_ESM.tif (236 kb)
Supplementary material 3 (TIFF 235 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Stephan Guggenhuber
    • 1
  • Alan Alpar
    • 2
    • 3
    • 4
  • Rongqing Chen
    • 5
  • Nina Schmitz
    • 1
  • Melanie Wickert
    • 1
  • Tobias Mattheus
    • 1
  • Anne E. Harasta
    • 1
    • 6
  • Martin Purrio
    • 1
  • Nadine Kaiser
    • 1
  • Maurice R. Elphick
    • 8
  • Krisztina Monory
    • 1
  • Werner Kilb
    • 5
  • Heiko J. Luhmann
    • 5
  • Tibor Harkany
    • 2
    • 7
  • Beat Lutz
    • 1
  • Matthias Klugmann
    • 1
    • 6
  1. 1.Institute of Physiological ChemistryUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
  2. 2.Division of Molecular Neurobiology, Department of Medical Biochemistry and BiophysicsKarolinska InstitutetStockholmSweden
  3. 3.Research Group of Experimental Neuroanatomy and Developmental BiologyHungarian Academy of SciencesBudapestHungary
  4. 4.Department of Anatomy, Histology and EmbryologySemmelweis UniversityBudapestHungary
  5. 5.Institute of PhysiologyUniversity Medical Center of the Johannes Gutenberg UniversityMainzGermany
  6. 6.Department of Physiology and Translational Neuroscience Facility, School of Medical SciencesUNSWSydneyAustralia
  7. 7.Department of Molecular Neuroscience, Center for Brain ResearchMedical University of ViennaViennaAustria
  8. 8.School of Biological and Chemical SciencesQueen Mary University of LondonLondonUK

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