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

Dudok, Barna; Barna, László; Ledri, Marco LU ; Szabó, Szilárd I; Szabadits, Eszter; Pintér, Balázs; Woodhams, Stephen G; Henstridge, Christopher M; Balla, Gyula Y and Nyilas, Rita, et al. (2015) In Nature Neuroscience 18(1). p.75-86
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... (More)

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.

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@article{dab96c01-f713-4c3b-bbea-652201678f40,
  abstract     = {<p>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.</p>},
  author       = {Dudok, Barna and Barna, László and Ledri, Marco and Szabó, Szilárd I and Szabadits, Eszter and Pintér, Balázs and Woodhams, Stephen G and Henstridge, Christopher M and Balla, Gyula Y and Nyilas, Rita and Varga, Csaba and Lee, Sang-Hun and Matolcsi, Máté and Cervenak, Judit and Kacskovics, Imre and Watanabe, Masahiko and Sagheddu, Claudia and Melis, Miriam and Pistis, Marco and Soltesz, Ivan and Katona, István},
  issn         = {1546-1726},
  keyword      = {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},
  language     = {eng},
  number       = {1},
  pages        = {75--86},
  publisher    = {Nature Publishing Group},
  series       = {Nature Neuroscience},
  title        = {Cell-specific STORM super-resolution imaging reveals nanoscale organization of cannabinoid signaling},
  url          = {http://dx.doi.org/10.1038/nn.3892},
  volume       = {18},
  year         = {2015},
}