Regulation of Neuronal Cell Adhesion Molecule Expression by NF-κB

Carol S Simpson,Brian J Morris

doi:10.1074/jbc.275.22.16879

Abstract

The neuronal cell adhesion molecule (NCAM) is a key mediator of structural plasticity in the central nervous system, but the mechanisms that control its expression are unknown. Equally, although the transcription factor NF-kappaB is present in the brain, few NF-kappaB-regulated genes relevant for central nervous system function have been identified. We have previously demonstrated that NF-kappaB is activated in neuronal cultures treated with kainic acid or nitric oxide. We show here that kainic acid or nitric oxide also increase the levels of NCAM mRNA and protein in neurons and that this induction of NCAM expression is sensitive to dexamethasone and to antisense, but not missense, oligonucleotides designed to suppress NF-kappaB synthesis. Nitric oxide also stimulates protein binding to an NF-kappaB site in the promoter of the NCAM gene. This indicates that NF-kappaB, which has recently been implicated in synaptic plasticity and also in the etiology of neurodegenerative disease, plays a crucial role in the activity-dependent regulation of NCAM gene expression. In addition, since both NCAM and NF-kappaB are present in the post-synaptic density, this represents a route allowing direct communication between the synapse and the nucleus.

Highlights

In all models of long-lasting synaptic plasticity, the later phases are dependent on the synthesis of new proteins
Exposure of striatal neurons to LPS, which activates NF-␬B in cultured cells, and kainic acid produced increases in neuronal cell adhesion molecule (NCAM)-ir (Fig. 1, c and d). These results demonstrate that the neuronal expression of the NCAM gene is subject to regulation by neurohumoral factors
Dexamethasone prevents the activation of the transcription factor NF-␬B [55], and we observed that in the absence of any neurotoxic effects, the increases in NCAM-ir protein levels caused by SNAP, LPS, and kainic acid were blocked by pretreatment with dexamethasone, (Fig. 2, a and b)

Summary

Introduction

In all models of long-lasting synaptic plasticity, the later phases are dependent on the synthesis of new proteins. The mechanisms involved in elevating NCAM expression are likely to be different from the post-transcriptional regulation of CamKII expression, since NCAM mRNA is not found in neuronal dendrites.2 Increased transcription of the NCAM gene is probably involved, since enhanced activation of AMPA/kainate receptors, which facilitate the induction of LTP and enhance learning, elevates the activity of the NCAM promoter [42].

Results

Conclusion