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AMPA receptors regulate transcription of the plasticity-related immediate-early gene Arc

Abstract

Learning and memory depend critically on long-term synaptic plasticity, which requires neuronal gene expression. In the prevailing view, AMPA receptors mediate fast excitatory synaptic transmission and effect short-term plasticity, but they do not directly regulate neuronal gene expression. By studying regulation of Arc, a gene required for long-term plasticity, we uncovered a new role for AMPA receptors in neuronal gene expression. Spontaneous synaptic activity or activity induced by brain-derived neurotrophic factor (BDNF) elicited Arc expression in cultures of rat cortical neurons and in organotypic brain slices. Notably, inhibiting AMPA receptors strongly potentiated activity-dependent Arc expression. We found that AMPA receptors negatively regulate Arc transcription, but not translation or stability, through a mechanism involving a pertussis toxin–sensitive G protein. These results provide insights into the activity-dependent mechanisms of Arc expression and suggest that, in addition to effecting short-term plasticity, AMPA receptors regulate genes involved in long-term plasticity.

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Figure 1: Primary cultured neurons recapitulate essential features of Arc regulation.
Figure 2: Synaptic activity is required for a component of BDNF-induced Arc expression.
Figure 3: AMPA receptor inhibition potentiates BDNF-induced expression of Arc.
Figure 4: The relative extent of NMDA and AMPA receptor activation determines Arc expression.
Figure 5: Pertussis toxin–sensitive G proteins, but not Src-family kinases, may mediate regulation of Arc expression by AMPA receptors.
Figure 6: AMPA receptor inhibition does not affect BDNF-induced Arc translation.
Figure 7: AMPA receptor inhibition does not stabilize Arc protein.
Figure 8: AMPA receptors regulate Arc expression at the level of transcription but not mRNA stability.

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Acknowledgements

We are grateful to Amgen, Inc. (Thousand Oaks, California) for providing recombinant human BDNF and to P. Worley (Johns Hopkins University School of Medicine, Baltimore) for providing Arc antiserum. Rat Arc cDNA was kindly provided by J. Guzowski (University of New Mexico School of Medicine, Albuquerque). GluR1 was a gift from D. Bredt (Eli Lilly, Indianapolis, Indiana), GFPu was a gift from R. Kopito (Stanford University, Stanford, California) and mRFP1 was a gift from R. Tsien (Howard Hughes Medical Institute, University of California, San Diego). We thank G. Howard and S. Ordway for editorial assistance, K. Nelson for administrative assistance and L. Mucke for comments on the manuscript. S.F. is supported by the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Aging and the J. David Gladstone Institutes. S.A.P. is supported by an NINDS National Research Service Award. J.C. is supported by a fellowship from the McBean Foundation. S.M. is supported by fellowships from the UCSF Hillblom Center for the Biology of Aging and from the Graduate Research and Education in Adaptive Bio-Technology Program under the auspices of the University of California System-Wide Biotechnology Research and Education Program. V.R.R., C.L.P. and S.M. are supported by the NIH-NIGMS UCSF Medical Scientist Training Program. This project was supported by the Epilepsy Foundation. The animal care facility was partly supported by an NIH Extramural Research Facilities Improvement Program Project.

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Contributions

S.A.P. contributed to experiments involving qfRT-PCR. J.C. prepared the organotypic slice cultures. C.L.P. performed the FISH experiments that involved immunostaining, and S.M. performed the experiments with GFPu. V.R.R. conducted all other experiments and data analysis, and V.R.R. and S.F. wrote the manuscript. S.F. supervised the project.

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Correspondence to Steven Finkbeiner.

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Supplementary information

Supplementary Fig. 1

Synaptic activity induced by TTX washout enhances calcium oscillations in cultured neurons (PDF 112 kb)

Supplementary Fig. 2

BDNF induces Arc protein expression in neurons, not glia (PDF 105 kb)

Supplementary Fig. 3

An L-VSCC antagonist does not potentiate BDNF-induced Arc protein expression (PDF 105 kb)

Supplementary Fig. 4

A specific antagonist of calcium-permeable AMPA receptors does not potentiate BDNF-induced Arc protein expression (PDF 177 kb)

Supplementary Fig. 5

AMPA receptors do not regulate signals sent by TrkB (PDF 254 kb)

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Rao, V., Pintchovski, S., Chin, J. et al. AMPA receptors regulate transcription of the plasticity-related immediate-early gene Arc. Nat Neurosci 9, 887–895 (2006). https://doi.org/10.1038/nn1708

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