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Allosteric modulation of ampa-type glutamate receptors increases activity of the promoter for the neural cell adhesion molecule, n-cam

Academic Article
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Overview

authors

  • Holst, B. D.
  • Vanderklish, Peter
  • Krushel, L. A.
  • Zhou, W.
  • Langdon, R. B.
  • McWhirter, J. R.
  • Edelman, Gerald
  • Crossin, Kathryn

publication date

  • March 1998

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • To study regulation in vivo of the promoter for the neural cell adhesion molecule, N-CAM, we have used homologous recombination to insert the bacterial lacZ gene between the transcription and translation initiation sites of the N-CAM gene. This insertion disrupts the gene and places the expression of beta-galactosidase under the control of the N-CAM promoter. Animals homozygous for the disrupted allele did not express N-CAM mRNA or protein, but the pattern of beta-galactosidase expression in heterozygous and homozygous embryos was similar to that of N-CAM mRNA in wild-type animals. The homozygotes exhibited many of the morphological abnormalities observed in previously reported N-CAM knockout mice, with the exception that hippocampal long-term potentiation in the Schaffer collaterals was identical in homozygous, heterozygous, and wild-type animals. Heterozygous mice were used to examine the regulation of the N-CAM promoter in response to enhanced synaptic transmission. Treatment of the mice with an ampakine, an allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that enhances normal glutamate-mediated synaptic transmission, increased the expression of beta-galactosidase in vivo as well as in tissue slices in vitro. Similar treatments also increased the expression of N-CAM mRNA in the heterozygotes. The effects of ampakine in slices were strongly reduced in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an AMPA receptor antagonist. Taken together, these results indicate that facilitation of AMPA receptor-mediated transmission leads to activation of the N-CAM promoter and provide support for the hypothesis that N-CAM synthesis is regulated in part by synaptic activity.

subject areas

  • Allosteric Regulation
  • Animals
  • Embryo, Mammalian
  • Excitatory Postsynaptic Potentials
  • Gene Expression Regulation
  • Heterozygote
  • Hippocampus
  • Homozygote
  • Long-Term Potentiation
  • Mice
  • Mice, Knockout
  • Neural Cell Adhesion Molecules
  • Organ Culture Techniques
  • Promoter Regions, Genetic
  • RNA, Messenger
  • Receptors, AMPA
  • Recombinant Fusion Proteins
  • Transcription, Genetic
  • beta-Galactosidase
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Identity

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.95.5.2597

PubMed ID

  • 9482932
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Additional Document Info

start page

  • 2597

end page

  • 2602

volume

  • 95

issue

  • 5

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