Cannabinoid receptor-mediated modulation of inhibitory inputs to mitral cells in the main olfactory bulb

Abstract

The endocannabinoid (eCB) signaling system has been functionally implicated in many brain regions. Our understanding of the role of cannabinoid receptor type 1 (CB$_1$) in olfactory processing remains limited. Cannabinoid signaling is involved in regulating glomerular activity in the main olfactory bulb (MOB). However, the cannabinoid-related circuitry of inputs to mitral cells in the MOB has not been fully determined. Using anatomical and functional approaches we have explored this question. CB$_1$ was present in periglomerular processes of a GAD65-positive subpopulation of interneurons but not in mitral cells. We detected eCBs in the mouse MOB as well as the expression of CB$_1$ and other genes associated with cannabinoid signaling in the MOB. Patch-clamp electrophysiology demonstrated that CB$_1$ agonists activated mitral cells and evoked an inward current, while CB$_1$ antagonists reduced firing and evoked an outward current. CB$_1$ effects on mitral cells were absent in subglomerular slices in which the olfactory nerve layer and glomerular layer were removed, suggesting the glomerular layer as the site of CB$_1$ action. We previously observed that GABAergic periglomerular cells show the inverse response pattern to CB$_1$ activation compared with mitral cells, suggesting that CB$_1$ indirectly regulates mitral cell activity as a result of cellular activation of glomerular GABAergic processes . This hypothesis was supported by the finding that cannabinoids modulated synaptic transmission to mitral cells. We conclude that CB$_1$ directly regulates GABAergic processes in the glomerular layer to control GABA release and, in turn, regulates mitral cell activity with potential effects on olfactory threshold and behavior.