Ephaptic coupling refers to interactions between neurons mediated by current flow through the extracellular space. Ephaptic interactions between axons are considered negligible, because of the relatively large extracellular space and the layers of myelin that separate most axons. By contrast, olfactory nerve axons are unmyelinated and arranged in tightly packed bundles, features that may enhance ephaptic coupling. We tested the hypothesis that ephaptic interactions occur in the mammalian olfactory nerve with the use of a computational approach. Numerical solutions of models of axon fascicles show that significant ephaptic interactions occur for a range of physiologically relevant parameters. An action potential in a single axon can evoke action potentials in all other axons in the fascicle. Ephaptic interactions can also lead to synchronized firing of independently stimulated axons. Our findings suggest that ephaptic interactions may be significant determinants of the olfactory code and that such interactions may occur in other, similarly organized axonal or dendritic bundles.

No abstract

Quinolinate is a tryptophan metabolite and an intermediary in nicotinamide adenine dinucleotide (NAD+) synthesis in hepatocytes. Kynurenine is an upstream metabolite in the same biochemical pathway. Under normal physiological conditions, kynurenine is thought to be produced primarily in the liver as an NAD+ precursor. However, during immune stimulation or inflammation, numerous extrahepatic tissues convert systemic tryptophan to kynurenine, and its concentration subsequently rises dramatically in blood. The fate and role of extrahepatic kynurenine are uncertain. In order to begin addressing this question, the present study was performed to determine which cell types can produce quinolinate from either systemic tryptophan or kynurenine. By using highly specific antibodies to protein-coupled quinolinate, we found that intraperitoneal injections of tryptophan led to increased quinolinate immunoreactivity primarily in hepatocytes, with moderate increases in tissue macrophages and splenic follicles. In contrast, intraperitoneal injections of kynurenine did not result in any significant increase in hepatocyte quinolinate immunoreactivity, but rather led to dramatic increases in immunoreactivity in tissue macrophages, splenic white pulp, and thymic medulla. These findings suggest that hepatocytes do not make significant use of extracellular kynurenine for quinolinate or NAD+ synthesis, and that, instead, extrahepatic kynurenine is preferentially metabolized by immune cells throughout the body. The possible significance of the preferential metabolism of kynurenine by immune cells during an immune response is discussed.

The small, unmyelinated axons of olfactory sensory neurons project to the olfactory bulb in densely packed fascicles, an arrangement conducive to axo-axonal interactions. We recently demonstrated ephaptic interactions between these axons in the olfactory nerve layer, the layer of the olfactory bulb in which the axon fascicles interweave and rearrange extensively. In the present study, we hypothesized that the axons, which express connexins, may have another mode of communication: gap junctions. Previous transmission electron microscopy (TEM) studies have failed to demonstrate such junctions. However, the definitive method for detecting gap junctions, freeze fracture, has not been used to examine the interaxonal connections of the olfactory nerve layer. Here, we apply a combined approach of TEM and freeze fracture to determine if gap junctions are present between the olfactory axons. Gap junctions involving olfactory axons were not found. However, by freeze fracture, P faces of both the axons and ensheathing cells (glia that surround the axon fascicles) contained distinctive linear arrays of particles, aligned along the small columns of extracellular space. In axons, few intramembranous particles were present outside of these arrays. Multi-helix proteins, including ion channels and connexin hemichannels, have been shown to be visible as particles by freeze fracture. This suggests that the proteins important for signal transmission are confined to the linear arrays. Such an arrangement would facilitate ephaptic transmission, calcium waves, current oscillations, and paracrine communication and may be important for olfactory neural code processing.Keywords freeze fracture; ultrastructure; olfactory bulb; ephaptic; connexins; hemichannels Olfactory receptor neurons project from the olfactory epithelium to the olfactory bulb by dense bundles of thin, unmyelinated olfactory axons (Marin-Padilla and Amieva, 1989;Daston et al., 1990;Mori, 1993). The high packing density of these axons and the absence of intervening glia suggest that olfactory coding may be affected by axoaxonal interactions.We recently demonstrated (Bokil et al., 2001) that neighboring axons are able to influence each other by ephaptic interactions-current spread through the small extracellular space. We have argued (Bokil et al., 2001) that ephaptic interactions, as well as interneuronal interactions mediated by extruded potassium ions (Bliss and Rosenberg, 1979) First, olfactory receptors of mature mammals are constantly regenerated (Graziadei and Graziadei, 1979;Graziadei and Monti Graziadei, 1983), and developing neurons of the central nervous system are often extensively coupled by gap junctions (reviewed in Kandler and Katz, 1995;Naus and Bani-Yaghoub, 1998;Chang and Balice-Gordon, 2000). Second, olfactory receptor neurons express connexins, the proteins that form gap junctions. Olfactory receptor neurons express mRNA for connexins 43 (Zhang et al., 2000), 45 (Zhang andRestrepo, 2002), and 36 (Zhang andRestrepo, 2003). Furthermore, in immun...