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NMDA receptors regulate developmental gap junction uncoupling via CREB signaling

Nature Neuroscience volume 8, pages 1720–1726 (2005)Cite this article

Abstract

Signaling through gap junctions (electrical synapses) is important in the development of the mammalian central nervous system. Abundant between neurons during postnatal development, gap junction coupling subsequently decreases and remains low in the adult, confined to specific subsets of neurons. Here we report that developmental uncoupling of gap junctions in the rat hypothalamus in vivo and in vitro is associated with a decrease in connexin 36 (Cx36) protein expression. Both developmental gap junction uncoupling and Cx36 downregulation are prevented by the blockade of NMDA glutamate receptors, action potentials and the calcium–cyclic AMP response element binding protein (CREB), and are accelerated by CREB overexpression. Developmental gap junction uncoupling and Cx36 downregulation are not affected by blockade of non-NMDA glutamate receptors, and do not occur in hypothalamic neurons from NMDA receptor subunit 1 (NMDAR1) knockout mice. These results demonstrate that NMDA receptor activity contributes to the developmental uncoupling of gap junctions via CREB-dependent downregulation of Cx36.

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Figure 1: Chronic NMDA receptor blockade by MK-801 reduces developmental gap junction uncoupling and Cx36 downregulation in the hypothalamus in vivo.
Figure 2: Chronic NMDA receptor blockade by AP5 prevents developmental gap junction uncoupling and Cx36 downregulation in hypothalamic neurons in vitro.
Figure 3: NMDAR1 knockout prevents developmental gap junction uncoupling and Cx36 downregulation.
Figure 4: Signal transduction pathways in developmental gap junction uncoupling.
Figure 5: Developmental gap junction uncoupling and Cx36 downregulation are mediated via CREB-dependent mechanisms.

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Acknowledgements

We are grateful to J. Denisova, E. Leininger, I.R. Popescu and T. Stuart for technical contributions and to R.L. Neve (Harvard Medical School) for supplying CREB viral vectors. This research was supported by a Louisiana Board of Regents Research Competitiveness Subprogram award to R.A.C.; and by a US National Institutes of Health grant (RO1 DA015088-01A1), a National Science Foundation grant (IBN-0117603) and an American Heart Association grant (0350530N) to A.B.B.

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Authors and Affiliations

  1. Department of Cell and Molecular Biology, Tulane University, New Orleans, 70118, Louisiana, USA

    Harsha Arumugam, Xinhuai Liu & Andrei B Belousov

  2. Department of Psychology, Tulane University, New Orleans, 70118, Louisiana, USA

    Paul J Colombo

  3. Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, New Orleans, 70112, Louisiana, USA

    Roderick A Corriveau

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Correspondence to Andrei B Belousov.

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Supplementary information

Supplementary Fig. 1

Initial developmental increase in gap junction coupling and Cx36 expression in the hypothalamus in vivo and in vitro. (PDF 347 kb)

Supplementary Fig. 2

Effects of NMDA on cytoplasmic Ca2+ activity in hypothalamic cultures obtained from wild–type and NMDAR1 knockout mice. (PDF 227 kb)

Supplementary Fig. 3

Transient developmental increase in gap junction coupling and Cx36 expression are mediated by action potential–dependent mechanisms. (PDF 117 kb)

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Arumugam, H., Liu, X., Colombo, P. et al. NMDA receptors regulate developmental gap junction uncoupling via CREB signaling. Nat Neurosci 8, 1720–1726 (2005). https://doi.org/10.1038/nn1588

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