A major challenge in neuroscience is to determine the nanoscale position and quantity of signalling 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 signalling 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 signalling at somatic versus dendritic synapses.

Furthermore, chronic Δ9-tetrahydrocannabinol administration, which reduces cannabinoid efficacy on GABA release, evoked marked CB1 down regulation 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 signalling and cannabis-induced cognitive dysfunction.

Source:Nature Neuroscience18,75–86(2015) doi:10.1038/nn.3892 Pub. online 08/12/14