Tonic endocannabinoid-mediated modulation of GABA release is independent of the CB1 content of axon terminals.

Nora Lenkey,Norbert Hájos,Tekla Kirizs,E Sylvester Vizi,Zoltán Máté,Gábor Szabó,Zoltan Nusser,Noemi Holderith

doi:10.1038/ncomms7557

Abstract

The release of GABA from cholecystokinin-containing interneurons is modulated by type-1 cannabinoid receptors (CB1). Here we tested the hypothesis that the strength of CB1-mediated modulation of GABA release is related to the CB1 content of axon terminals. Basket cell boutons have on average 78% higher CB1 content than those of dendritic-layer-innervating (DLI) cells, a consequence of larger bouton surface and higher CB1 density. The CB1 antagonist AM251 caused a 54% increase in action potential-evoked [Ca2+] in boutons of basket cells, but not in DLI cells. However, the effect of AM251 did not correlate with CB1 immunoreactivity of individual boutons. Moreover, a CB1 agonist decreased [Ca2+] in a cell type- and CB1-content-independent manner. Replica immunogold labelling demonstrated the colocalization of CB1 with the Cav2.2 Ca2+ channel subunit. Our data suggest that only a subpopulation of CB1s, within nanometre distances from their target Cav2.2 channels, are responsible for endocannabinoid-mediated modulation of GABA release.

Highlights

The release of GABA from cholecystokinin-containing interneurons is modulated by type-1 cannabinoid receptors (CB1)
In low-magnification light microscopic (LM) images of hippocampal sections immunolabelled for CB1, the stratum pyramidale in the distal CA3 appeared more intensely labelled in many slices than either the dendritic layers or the stratum pyramidale of the proximal CA3
We report the first investigation of the ‘number–function’ relationship for a metabotropic receptor in a small subcellular compartment of a central neuron; CB1 on axon terminals of CCK-expressing hippocampal GABAergic INs

Summary

Introduction

The release of GABA from cholecystokinin-containing interneurons is modulated by type-1 cannabinoid receptors (CB1). Correspondence and requests for materials should be addressed to Z.N. The effect of a neuroactive substance on its target cells depends on its spatio-temporal concentration profile, its affinity to the receptors and the number of receptors on the target cells. The effect of a neuroactive substance on its target cells depends on its spatio-temporal concentration profile, its affinity to the receptors and the number of receptors on the target cells According to this simple view, the more receptors a cell expresses on its surface, the larger the effect of the ligand. G-protein-coupled receptors (GPCRs) form a diverse family, with hundreds of genes expressed in the central nervous system[9]

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Conclusion