Ultrastructural Localization of Neuronal Brain CB2 Cannabinoid Receptors

Abstract

The functional expression of neuronal CB2 cannabinoid receptors (CB2-Rs) in the brain has been controversial. We and others have now demonstrated that CB2-Rs are expressed in neurons and glial cells in the brain. However, the subcellular localization of these receptors has not been characterized. In this study we used immunohistochemical electron microscopy to determine the subcellular distribution of CB2-Rs in two brain regions. Brain sections from the CA1 hippocampal area and substantia nigra were immunostained for CB2-Rs and analyzed by electron microscopy. In each region immunoperoxidase labeling for CB2-Rs was detected in neurons as well as in glial and endothelial cells. In neuronal cells, CB2-R immunoreactivity was observed in somata and large and medium-sized dendrites. In the soma, the CB2-R labeling was mainly associated with the rough endoplasmic reticulum and Golgi apparatus, suggesting its endogenous synthesis. In the dendrites, the CB2-R labeling was observed in the cytoplasm and was associated with the plasma membrane near the area of synaptic contact with axon terminals, indicating a postsynaptic distribution of these receptors. In CB2-Rs in immunoreactive glial and endothelial cells, the labeling was also found to be associated with the plasma membrane. In the substantia nigra, some unmyelinated axons were immunoreactive for CB2-Rs, but we rarely found CB2-R-labeled axon terminals. These results extend our previous detection of postsynaptic cortical CB2-Rs and provide additional ultrastructural evidence that CB2-Rs are mainly postsynaptic in the CA1 area of the hippocampus and substantia nigra. The functional implication of pre- and/or postsynaptic localization of CB2-Rs remains to be determined.

Excitability of prefrontal cortical pyramidal neurons is modulated by activation of intracellular type-2 cannabinoid receptors

“…A report by Currie et al (32) shows the intracellular localization of functional CB 2 Rs in guinea pig heart cells. Others report that CB 2 Rs are associated with the rough endoplasmic reticulum and Golgi apparatus in hippocampal pyramidal neurons, but in these studies, the functional role of intracellular CB 2 Rs was not investigated (25,26,28).…”

“…Furthermore, this opening of CaCCs is most likely responsible for the observed reduction in neuronal excitability upon CB 2 R activation. The presence of CB 2 R mRNA in the brain and CB 2 Rs in neurons of the brainstem, the cerebellum, and the hippocampus has been reported (12,13,18,(25)(26)(27)(28), but their presence in the cortex remained to be further characterized. The current view on the presence of functional CB 2 Rs in the CNS supports the expression of CB 2 Rs in neurons essentially upon brain stress and damage (19).…”

CB2 Cannabinoid Receptor Agonist Ameliorates Alzheimer-Like Phenotype in AβPP/PS1 Mice

“…extensive range of natural and synthetic cannabinoids, major attention in AD has been paid to CB 2 receptor specific agonists because of their lack of psychoactive properties. CB 2 receptors are mainly expressed in the immune system, including microglial cells [9,10], but relatively lower expression of CB 2 receptors in neurons has been proposed as well [11][12][13][14]. In AD postmortem brains, CB 2 receptors have been reported to be overexpressed in A␤ plaques-associated microglia, suggesting these receptors as potential therapeutic targets [15].…”

Cannabinoid Receptors CB1 and CB2 Form Functional Heteromers in Brain

“…The related receptor, CB 2 , traditionally was thought to be expressed in peripheral tissue, where it can help control inflammation and various immunological responses (1), but recent reports have suggested that it too can be found in the brain (albeit at a lower expression level than CB 1 receptors) (29) and can impact a variety of neuronal processes. Multiple studies have demonstrated the expression of CB 2 receptors in different non-neuronal (30 -33) and neuronal populations (31, 34 -38) where CB 2 receptors show a preferred postsynaptic localization (31,(35)(36)(37).…”