Refinement of odor molecule tuning by dendrodendritic synaptic inhibition in the olfactory bulb.

Mitral/tufted cells (M/T cells) and granule cells form reciprocal dendrodendritic synapses in the main olfactory bulb; the granule cell is excited by glutamate from the M/T cell and in turn inhibits M/T cells by gamma-aminobutyrate. The trans-synaptically excited granule cell is thought to induce lateral inhibition in neighboring M/T cells and to refine olfactory information. It remains, however, elusive how significantly and specifically this synaptic regulation contributes to the discrimination of different olfactory stimuli. This investigation concerns the mechanism of olfactory discrimination by single unit recordings of responses to a series of normal aliphatic aldehydes from individual rabbit M/T cells. This analysis revealed that inhibitory responses are evoked in a M/T cell by a defined subset of odor molecules with structures closely related to the excitatory odor molecules. Furthermore, blockade of the reciprocal synaptic transmission by the glutamate receptor antagonist or the gamma-aminobutyrate receptor antagonist markedly suppressed the odor-evoked inhibition, indicating that the inhibitory responses are evoked by lateral inhibition via the reciprocal synaptic transmission. The synaptic regulation in the olfactory bulb thus greatly enhances the tuning specificity of odor responses and would contribute to discrimination of olfactory information.

Induction of the gene encoding mucosal vascular addressin cell adhesion molecule 1 by tumor necrosis factor alpha is mediated by NF-kappa B proteins.

Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is involved in trafficking of lymphocytes to mucosal endothelium. Expression of MAdCAM-1 is induced in the murine endothelial cell line bEnd.3 by tumor necrosis factor alpha (TNF-alpha), interleukin 1, and bacterial lipopolysaccharide. Here we show that TNF-alpha enhances expression of a firefly luciferase reporter directed by the MAdCAM-1 promoter, confirming transcriptional regulation of MAdCAM-1. Mutational analysis of the promoter indicates that a DNA fragment extending from nt -132 to nt +6 of the gene is sufficient for TNF-alpha inducibility. Two regulatory sites critical for TNF-alpha induction were identified in this region. DNA-binding experiments demonstrate that NF-kappa B proteins from nuclear extracts of TNF-alpha-stimulated bEnd.3 cells bind to these sites, and transfection assays with promoter mutants of the MAdCAM-1 gene indicate that occupancy of both sites is essential for promoter function. The predominant NF-kappa B binding activity detected with these nuclear extracts is a p65 homodimer. These findings establish that, as with other endothelial cell adhesion molecules, transcriptional induction of MAdCAM-1 by TNF-alpha requires activated NF-kappa B proteins.