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 Δ9-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 Δ9-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.
|Number of pages||12|
|State||Published - Jan 1 2015|
Bibliographical noteFunding Information:
We are grateful to E. Tischler and G. Goda for their excellent technical assistance, I. Mihály for bouton distribution analysis, and C. Cserép and C. Fekete for their help with immunostaining and antibody labeling protocols. The authors are indebted to A. Zimmer (University of Bonn) for providing the CB1 knockout mouse line and to A. Tímár for his help with software analysis. We also thank N. Hájos, N. Holderith, N. Lenkey and Z. Nusser for their comments on the manuscript. The help of the Nikon Microscopy Center at the Institute of Experimental Medicine, Nikon Europe B.V., Nikon Austria GmbH and Auro-Science Consulting is greatly acknowledged for kindly providing microscopy support. This study was primarily supported by the European Research Council Grant 243153 and by the Momentum Program (LP2013-54/2013) of the Hungarian Academy of Sciences to I. Katona. The project was also funded by the Hungarian Academy of Sciences Equipment Grant (IF-22/2012) for super-resolution microscopy. I. Katona is a recipient of the Wellcome Trust International Senior Research Fellowship (090946/Z/09/Z). Additional support was provided by the US National Institutes of Health (NS74432) to I.S., and by the Italian Ministry of University (Grant PRIN 2009: 200928EEX4) and “Fondazione Banco di Sardegna” to M.P.
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ASJC Scopus subject areas
- Neuroscience (all)