Abstract
Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) catalyse the hydrolysis of the endocannabinoids anandamide and 2-arachidonoyl glycerol. We investigated their ultrastructural distribution in brain areas where the localization and effects of cannabinoid receptor activation are known. In the hippocampus, FAAH was present in somata and dendrites of principal cells, but not in interneurons. It was located mostly on the membrane surface of intracellular organelles known to store Ca(2+) (e.g. mitochondria, smooth endoplasmic reticulum), less frequently on the somatic or dendritic plasma membrane. MGL immunoreactivity was found in axon terminals of granule cells, CA3 pyramidal cells and some interneurons. In the cerebellum, Purkinje cells and their dendrites are intensively immunoreactive for FAAH, together with a sparse axon plexus at the border of the Purkinje cell/granule cell layers. Immunostaining for MGL was complementary, the axons in the molecular layer were intensively labelled leaving the Purkinje cell dendrites blank. FAAH distribution in the amygdala was similar to that of the CB(1) cannabinoid receptor: evident signal in neuronal somata and proximal dendrites in the basolateral nucleus, and hardly any labelling in the central nucleus. MGL staining was restricted to axons in the neuropil, with similar relative signal intensities seen for FAAH in different nuclei. Thus, FAAH is primarily a postsynaptic enzyme, whereas MGL is presynaptic. FAAH is associated with membranes of cytoplasmic organelles. The differential compartmentalization of the two enzymes suggests that anandamide and 2-AG signalling may subserve functional roles that are spatially segregated at least at the stage of metabolism.
Highlights
The identity and localization of cannabinoid receptors as well as their endogenous ligands have been recently reported (Devane et al, 1988,1992; Matsuda et al, 1990; Stella et al, 1997)
The major finding of our study is that Fatty acid amide hydrolase (FAAH) is localized in the somadendritic compartment, whereas monoglyceride lipase (MGL) is localized in axons
In the hippocampus and cerebellum FAAH is located primarily on the cytosolic surface of smooth endoplasmic reticulum cisternae and mitochondrial outer membranes, with only a very small proportion of the enzyme associated with cell membranes
Summary
The identity and localization of cannabinoid receptors as well as their endogenous ligands have been recently reported (Devane et al, 1988,1992; Matsuda et al, 1990; Stella et al, 1997). Activity-dependent release of endocannabinoids from hippocampal pyramidal and cerebellar Purkinje cells activate cannabinoid receptors located on excitatory and inhibitory axon terminals (Katona et al, 1999), and reduce c-aminobutyric acid (GABA; Hajos et al, 2000; Hoffman & Lupica, 2000) and glutamate (Shen et al, 1996; Misner & Sullivan, 1999) release. Recent experiments suggest that retrograde modulation of glutamatergic and GABAergic transmission may involve different cannabinoid receptors. CB1 is selectively located in GABAergic axons (Katona et al, 1999), Received 19 March 2004, revised 7 April 2004, accepted 13 April 2004 whereas glutamate release is regulated by a so far unidentified receptor (Hajos et al, 2001). Activation of N-methyl-daspartate receptors increases 2-AG levels but has no effect on anandamide formation, which requires instead the simultaneous activation of N-methyl-d-aspartate and a-7 nicotinic receptors (Stella & Piomelli, 2001)
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