Journal Article

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

Ledri, Marco, Henstridge, Christopher M, Szabadits, Eszter, Lee, Sang-Hun, Cervenak, Judit, Melis, Miriam, Szabó, Szilárd I, Soltesz, Ivan, Kacskovics, Imre, Woodhams, Stephen G, Nyilas, Rita, Varga, Csaba, Watanabe, Masahiko, Katona, István, Balla, Gyula Y, Dudok, Barna, Pistis, Marco, Barna, László, Pintér, Balázs, Matolcsi, Máté, Sagheddu, Claudia

2015

Overview

Combining patch-clamp recordings and subsequent STORM imaging of individual cells, the authors show that the axon terminals of perisomatically- and dendritically-projecting GABAergic interneurons show differences in CB 1 receptor number, active zone complexity, and receptor:effector ratio. Chronic exposure to THC evoked a dose-dependent and long-lasting downregulation of CB 1 at these synapses. 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 CB 1 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 CB 1 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 14 / 14/19 / 14/28 / 14/63 / 631/378/340 / Animal Genetics and Genomics / Animals / Behavioral Sciences / Biological Techniques / Biomedicine / Cannabinoid CB1 receptors / Cannabinoids / Cannabinoids - pharmacology / Cannabis / Cell research / Cellular signal transduction / Chemical properties / Chronic exposure / Cognition disorders / Cognitive ability / Comparative analysis / Complexity / Dose-Response Relationship, Drug / GABA / gamma-Aminobutyric Acid - physiology / Genetic aspects / HEK293 Cells / Hippocampus - physiology / Hippocampus - ultrastructure / Humans / Image Processing, Computer-Assisted - methods / Image resolution / Interneurons / Interneurons - physiology / Male / Marijuana / Methods / Mice / Mice, Inbred C57BL / Microscope and microscopy / Microscopy / Nanotechnology / Nervous system / Neurobiology / Neuroimaging / Neuroimaging - methods / Neurosciences / Physiological aspects / Physiology / Presynapse / Presynaptic Terminals - physiology / Presynaptic Terminals - ultrastructure / Receptor, Cannabinoid, CB1 - drug effects / Receptors / Receptors, Cannabinoid - physiology / Receptors, Cannabinoid - ultrastructure / Risk factors / Signal Transduction - physiology / Signaling / Synapses / Synapses - physiology / Synapses - ultrastructure / Terminals / Tetrahydrocannabinol / THC / γ-Aminobutyric acid