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Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons

Nature Neuroscience volume 13, pages 1090–1097 (2010)Cite this article

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Abstract

Homeostatic synaptic scaling alters the strength of synapses to compensate for prolonged changes in network activity and involves both excitatory and inhibitory neurons. The immediate-early gene Narp (neuronal activity–regulated pentraxin) encodes a secreted synaptic protein that can bind to and induce clustering of AMPA receptors (AMPARs). We found that Narp prominently accumulated at excitatory synapses on parvalbumin-expressing interneurons (PV-INs). Increasing network activity resulted in a homeostatic increase of excitatory synaptic strength onto PV-INs that increased inhibitory drive and this response was absent in neurons cultured from Narp−/− mice. Activity-dependent changes in the strength of excitatory inputs on PV-INs in acute hippocampal slices were also dependent on Narp and Narp−/− mice had increased sensitivity to kindling-induced seizures. We propose that Narp recruits AMPARs at excitatory synapses onto PV-INs to rebalance network excitation/inhibition dynamics following episodes of increased circuit activity.

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Figure 1: Narp expression is highly enriched at excitatory synapses on PV-INs.
Figure 2: Narp expression on PV-INs is dynamically regulated by activity.
Figure 3: Narp is derived from presynaptic neurons that contact PV-INs.
Figure 4: Disruption of perineuronal nets results in loss of surface Narp accumulation.
Figure 5: Narp modulates GluR4 on PV-INs in an activity-dependent manner.
Figure 6: Narp is required for homeostatic scaling of excitatory synaptic inputs onto PV-INs and regulates their spontaneous firing frequency.
Figure 7: Narp regulates PV-IN synaptic strength in acute hippocampal slices.
Figure 8: Narp−/− mice are hypersensitive to kindling-induced seizures.

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Acknowledgements

We thank M.S. Perin for the Narp−/− mouse, R.L. Huganir (Johns Hopkins University) for antibodies to GluR1, M. Dehoff and P. Chuang for animal care, M. Papapavlou for administrative assistance and X. Yuan and B. Jeffries for technical assistance. Work in the laboratory of C.J.M. is supported by a US National Institutes of Health intramural award. Work in the laboratory of P.F.W. is supported by US National Institutes of Health grants PAR-02-059 and NS 39156.

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Author notes

  1. Joo Min Park, Kenneth A Pelkey and Heidi L Grabenstatter: These authors contributed equally to this work.

Authors and Affiliations

  1. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Michael C Chang, Joo Min Park, Desheng Xu, David J Linden & Paul F Worley

  2. Laboratory of Cellular and Synaptic Neurophysiology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

    Kenneth A Pelkey & Chris J McBain

  3. Department of Neurology, University of Wisconsin, Madison, Wisconsin, USA

    Heidi L Grabenstatter & Thomas P Sutula

  4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Paul F Worley

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Contributions

M.C.C. designed the experiments, carried out the in vitro immunocytochemical and biochemical studies and analysis and wrote the bulk of the manuscript. J.M.P. performed the in vitro electrophysiological experiments and analysis and contributed to the manuscript. K.A.P. performed the slice electrophysiological experiments and analysis and contributed to the manuscript. H.L.G. performed the kindling experiments and analysis and contributed to the manuscript. D.X. provided reagents and helped with the discussion. P.F.W., D.J.L., T.P.S. and C.J.M. directed the project.

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Correspondence to Paul F Worley.

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Chang, M., Park, J., Pelkey, K. et al. Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons. Nat Neurosci 13, 1090–1097 (2010). https://doi.org/10.1038/nn.2621

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