Interrelationships between Somatostatin sst2A Receptors and Somatostatin-Containing Axons in Rat Brain: Evidence for Regulation of Cell Surface Receptors by Endogenous Somatostatin

Abstract

Using an antipeptide antibody, we reported previously on the distribution of the somatostatin sst2A receptor subtype in rat brain. Depending on the region, immunolabeled receptors were either confined to neuronal perikarya and dendrites or distributed diffusely in tissue. To investigate the functional significance of these distribution patterns, we examined the regional and cellular relationships between somatostatin axons and sst2A receptors in the rat CNS, using double-labeling immunocytochemistry. Light and confocal microscopy revealed a significant correlation ( p Ͻ 0.02) between the distribution of somatodendritic sst2A receptor immunoreactivity and that of somatostatin terminal fields, both quantitatively and qualitatively. Furthermore, in regions of somatodendritic labeling, a subpopulation of sst2A-immunoreactive cells was also immunopositive for somatostatin, suggesting that a subset of sst2A receptors consists of autoreceptors. By contrast, in regions displaying diffuse sst2A labeling only moderate to low densities of somatostatin terminals were observed, and no significant relationship was found between terminal density and receptor immunoreactivity.At the electron microscopic level, areas expressing somatodendritic sst2A labeling were found by immunogold cytochemistry to display low proportions of membrane-associated, as compared with intracellular, receptors. Conversely, in regions displaying diffuse sst2A receptor labeling, receptors were predominantly associated with neuronal plasma membranes, a finding consistent with the high density of sst2 binding sites previously visualized in these areas by autoradiography. Double-labeling studies demonstrated that in the former but not in the latter regions, sst2A-immunoreactive somata and dendrites were heavily contacted by somatostatin axon terminals. Taken together, these results suggest that the low incidence of membrane-associated receptors observed in regions of somatodendritic sst2A labeling may be caused by downregulation of cell surface receptors by endogenous somatostatin, possibly through ligand-induced receptor internalization.

Antidepressants Influence Somatostatin Levels and Receptor Pharmacology in Brain

“…Subsequent SRIF measurements in each cortical layer examined in the autoradiography studies were not attempted fearing low protein concentrations and inability to obtain results. In cortex and hippocampus, the sst 2A receptor has been shown to internalize in response to SRIF release (Dournaud et al, 1998) and to be involved in the neuronal endocytosis of SRIF (Stroh et al, 2000). The present data clearly suggest such an internalization of the sst 2 receptors in the cortical layers as a result of the increases in SRIF levels.…”

“…The hippocampal formation contains sst 1/4 subtypes, with the CA1 expressing predominantly the sst 4 subtype (Thoss et al, 1995;Videau et al, 2003). sst 2A receptor immunoreactivity was most prominent in the Tu, layers II-III of the cerebral cortex, NAc, pyramidal cells of CA1-2 subfields of the hippocampus, central and cortical amygdaloid nuclei (Dournaud et al, 1998;Schindler et al, 1998;Schulz et al, 2000).…”

Differential Subcellular Localization of mGluR1a and mGluR5 in the Rat and Monkey Substantia Nigra

“…As discussed in our previous study (Hanson and Smith, 1999), three possibilities should be considered: (1) extrasynaptic diffusion of glutamate from subthalamonigral synapses (Asztely et al, 1997;Barbour and Hausser, 1997), (2) release of glutamate from astrocytes (Antanitus, 1998;Araque et al, 1999), and (3) corelease of GABA and glutamate from striatonigral terminals (Dubinsky, 1989;White et al, 1994). The extrasynaptic localization of G-protein-coupled receptors is a general phenomenon in the CNS (Yung et al, 1995;Gracy et al, 1997;Dournaud et al, 1998;Bernard et al, 1999). Although the functions and mechanisms of activation of these receptors still remain to be established, their pattern of distribution indicates that they may play much more subtle and complex modulatory functions in neuronal activity than previously thought.…”

“…For instance, the muscarinic receptor m4 is primarily expressed intracellularly in cholinergic interneurons and projection neurons in the matrix compartment of the rat striatum under basal conditions (Bernard et al, 1999). Similarly, the somatostatin receptor sst2A displays a preferential cytoplasmic localization in neurons that receive dense somatostatin innervation (Dournaud et al, 1998). In general, G-protein-coupled receptors, including mGluR5, become internalized after agonist administration (Mantyh et al, 1995;Bernard et al, 1998Bernard et al, , 1999Dournaud et al, 1998;Dumartin et al, 1998;Lissin et al, 1999;Liu and Kirchgessner, 2000).…”

“…Similarly, the somatostatin receptor sst2A displays a preferential cytoplasmic localization in neurons that receive dense somatostatin innervation (Dournaud et al, 1998). In general, G-protein-coupled receptors, including mGluR5, become internalized after agonist administration (Mantyh et al, 1995;Bernard et al, 1998Bernard et al, , 1999Dournaud et al, 1998;Dumartin et al, 1998;Lissin et al, 1999;Liu and Kirchgessner, 2000). However, in these conditions, the receptors are initially localized on the plasma membrane in which, presumably, they could be activated by neurotransmitters in the extracellular space.…”