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The Journal of Neuroscience, May 3, 2006, 26(18):4870-4879; doi:10.1523/JNEUROSCI.4527-05.2006

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Development/Plasticity/Repair
Regulation of Nuclear Factor B in the Hippocampus by Group I Metabotropic Glutamate Receptors

Kenneth J. O’Riordan,¹ I-Chia Huang,¹ Marina Pizzi,³ PierFranco Spano,³ Flora Boroni,³ Regula Egli,¹ Priyanka Desai,¹ Olivia Fitch,¹ Lauren Malone,¹ Hyung Jin Ahn,² Hsiou-Chi Liou,⁴ J. David Sweatt,¹ and Jonathan M. Levenson¹

Departments of ¹Neuroscience and ²Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, ³Division of Pharmacology and Experimental Therapeutics, Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, 25123 Brescia, Italy, and ⁴Department of Immunology, Weill Medical College of Cornell University, New York, New York 10021

Correspondence should be addressed to Jonathan M. Levenson, Department of Pharmacology and The Waisman Center, University of Wisconsin School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706. Email: jlevenson{at}wisc.edu

An increasing amount of evidence suggests that the family of nuclear factor B (NF-B) transcription factors plays an important role in synaptic plasticity and long-term memory formation. The present study investigated the regulation of NF-B family members p50, p65/RelA, and c-Rel in the hippocampus in response to metabotropic glutamate receptor (mGluR) signaling. Activation of group I metabotropic glutamate receptors (GpI-mGluRs) with the agonist (S)-3,5-dihydroxyphenylglycine (DHPG) resulted in a time-dependent increase in DNA binding activity of p50, p65, and c-Rel in area CA1 of the hippocampus. An antagonist of mGluR5, 2-Methyl-6-(phenylethynyl)pyridine, inhibited the DHPG-induced activation of NF-B, whereas an antagonist of mGluR1, (S)-(+)--amino-4-carboxy-2-methylbenzeneacetic acid, did not. Using a series of inhibitors, we investigated the signaling pathways necessary for DHPG-induced activation of NF-B and found that they included the phosphatidyl inositol 3-kinase, protein kinase C, mitogen-activated protein kinase kinase, and p38-mitogen-activated protein kinase pathways. To determine the functional significance of mGluR-induced regulation of NF-B, we measured long-term depression (LTD) of Schaffer-collateral synapses in the hippocampus of c-Rel knock-out mice. Early phase LTD was normal in c-rel^–/– mice. However, late-phase LTD (>90 min) was impaired in c-rel^–/– mice. The observations of this deficit in hippocampal synaptic plasticity prompted us to further investigate long-term memory formation in c-rel^–/– mice. c-rel^–/– mice exhibited impaired performance in a long-term passive avoidance task, providing additional evidence for c-Rel in long-term memory formation. These results demonstrate that the NF-B transcription factor family is regulated by GpI-mGluRs in the hippocampus and that the c-Rel transcription factor is necessary for long-term maintenance of LTD and formation of long-term memory.

Key words: NF-B; hippocampus; long-term depression; metabotropic glutamate receptor; c-Rel; memory

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Received Oct. 22, 2005; revised March 28, 2006; accepted April 1, 2006.

Correspondence should be addressed to Jonathan M. Levenson, Department of Pharmacology and The Waisman Center, University of Wisconsin School of Medicine and Public Health, 1300 University Avenue, Madison, WI 53706. Email: jlevenson{at}wisc.edu

This article has been cited by other articles:

				H. J. Ahn, C. M. Hernandez, J. M. Levenson, F. D. Lubin, H.-C. Liou, and J. D. Sweatt c-Rel, an NF-{kappa}B family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation Learn. Mem., July 11, 2008; 15(7): 539 - 549. [Abstract] [Full Text] [PDF]

				G. E. Stutzmann The Pathogenesis of Alzheimers Disease Is It a Lifelong "Calciumopathy"? Neuroscientist, October 1, 2007; 13(5): 546 - 559. [Abstract] [PDF]

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