Cell-specific STORM super-resolution imaging reveals nanoscale organization of cannabinoid signaling

Research output: Contribution to journalArticle

Abstract

A major challenge in neuroscience is to determine the nanoscale position and quantity of signaling molecules in a cell type- and subcellular compartment-specific manner. We developed a new approach to this problem by combining cell-specific physiological and anatomical characterization with super-resolution imaging and studied the molecular and structural parameters shaping the physiological properties of synaptic endocannabinoid signaling in the mouse hippocampus. We found that axon terminals of perisomatically projecting GABAergic interneurons possessed increased CB1 receptor number, active-zone complexity and receptor/effector ratio compared with dendritically projecting interneurons, consistent with higher efficiency of cannabinoid signaling at somatic versus dendritic synapses. Furthermore, chronic Δ(9)-tetrahydrocannabinol administration, which reduces cannabinoid efficacy on GABA release, evoked marked CB1 downregulation in a dose-dependent manner. Full receptor recovery required several weeks after the cessation of Δ(9)-tetrahydrocannabinol treatment. These findings indicate that cell type-specific nanoscale analysis of endogenous protein distribution is possible in brain circuits and identify previously unknown molecular properties controlling endocannabinoid signaling and cannabis-induced cognitive dysfunction.

Details

Authors
  • Barna Dudok
  • László Barna
  • Szilárd I Szabó
  • Eszter Szabadits
  • Balázs Pintér
  • Stephen G Woodhams
  • Christopher M Henstridge
  • Gyula Y Balla
  • Rita Nyilas
  • Csaba Varga
  • Sang-Hun Lee
  • Máté Matolcsi
  • Judit Cervenak
  • Imre Kacskovics
  • Masahiko Watanabe
  • Claudia Sagheddu
  • Miriam Melis
  • Marco Pistis
  • Ivan Soltesz
  • István Katona
External organisations
  • Hungarian Academy of Sciences
  • University of Cagliari
Research areas and keywords

Keywords

  • Animals, Cannabinoids, Dose-Response Relationship, Drug, HEK293 Cells, Hippocampus, Humans, Image Processing, Computer-Assisted, Interneurons, Male, Mice, Mice, Inbred C57BL, Neuroimaging, Presynaptic Terminals, Receptor, Cannabinoid, CB1, Receptors, Cannabinoid, Signal Transduction, Synapses, gamma-Aminobutyric Acid, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Original languageEnglish
Pages (from-to)75-86
Number of pages12
JournalNature Neuroscience
Volume18
Issue number1
Publication statusPublished - 2015 Jan
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes