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A single fear-inducing stimulus induces a transcription-dependent switch in synaptic AMPAR phenotype

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Abstract

Changes in emotional state are known to alter neuronal excitability and can modify learning and memory formation. Such experience-dependent neuronal plasticity can be long-lasting and is thought to involve the regulation of gene transcription. We found that a single fear-inducing stimulus increased GluR2 (also known as Gria2) mRNA abundance and promoted synaptic incorporation of GluR2-containing AMPA receptors (AMPARs) in mouse cerebellar stellate cells. The switch in synaptic AMPAR phenotype was mediated by noradrenaline and action potential prolongation. The subsequent rise in intracellular Ca2+ and activation of Ca2+-sensitive ERK/MAPK signaling triggered new GluR2 gene transcription and a switch in the synaptic AMPAR phenotype from GluR2-lacking, Ca2+-permeable receptors to GluR2-containing, Ca2+-impermeable receptors on the order of hours. The change in glutamate receptor phenotype altered synaptic efficacy in cerebellar stellate cells. Thus, a single fear-inducing stimulus can induce a long-term change in synaptic receptor phenotype and may alter the activity of an inhibitory neural network.

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Figure 1: An olfactory stimulus altered synaptic AMPA receptor subtype and expression of GluR2 mRNA in stellate cells.
Figure 2: β-adrenergic receptors mediated the olfactory stimulus–induced change in synaptic AMPA receptor subtype.
Figure 3: Noradrenaline induced a change in synaptic AMPA receptor phenotype.
Figure 4: Increasing the action potential duration in stellate cells induces a change in rectification of the I-V relationship.
Figure 5: Noradrenaline increases Ca influx during the action potential and Ca entry via L-type Ca channels is required for noradrenaline-induced change in AMPAR phenotype.
Figure 6: Activation of ERK-dependent pathways and gene transcription are required for the noradrenaline and action potential broadening–induced change in sEPSC rectification.
Figure 7: Noradrenaline and TEA treatment increased the level of GluR2, but not GluR1, mRNA expression (n = 5).

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Change history

  • 17 January 2010

    In the version of this article initially published, the gene Ppia (cyclophilin A) was incorrectly written in the Online Methods as p-ia. The sentence “Two house keeping protein genes, Gapdh and p-ia, were tested and showed no detectable change following fox urine exposure, and were therefore used in our experiments” should read “Two house keeping protein genes, Gapdh and Ppia (encoding cyclophilin A), were tested and showed no detectable change following fox urine exposure, and were therefore used in our experiments”. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank D. Grove and S. Acharjee for scientific input, and M.V.L. Bennett, B. Luscher, P.E. Castillo, L.K. Kaczmarek and M. Whim for helpful discussions and comments on the manuscript. This work was supported by National Science Foundation grant IBN-0344559 and US National Institutes of Health grant NS58867 (S.Q.J.L.) and by US National Institutes of Health grant NS46742 (R.S.Z.). R.S.Z. is the F.M. Kirby Professor in Neural Repair and Protection.

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Y.L. designed and conducted the behavioral, electrophysiological and real-time single-cell RT-PCR experiments, prepared figures and participated in writing the manuscript. L.F. designed and carried out the in situ hybridization assays. I.S. performed the behavioral, real-time single-cell RT-PCR and some electrophysiology experiments, analyzed in situ hybridization data, and prepared figures. Y.T. helped to perform the in situ hybridization assays and participated in data collection and analysis. G.S. provided GAD65-GFP mice. R.S.Z. supervised the in situ hybridization experiments and contributed to the writing and editing of the manuscript. S.J.L. conceived and designed the study and wrote the manuscript.

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Correspondence to Siqiong June Liu.

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Liu, Y., Formisano, L., Savtchouk, I. et al. A single fear-inducing stimulus induces a transcription-dependent switch in synaptic AMPAR phenotype. Nat Neurosci 13, 223–231 (2010). https://doi.org/10.1038/nn.2474

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