Letter | Published:

The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition

Nature volume 503, pages 121125 (07 November 2013) | Download Citation

Abstract

A heterogeneous population of inhibitory neurons controls the flow of information through a neural circuit1,2,3. Inhibitory synapses that form on pyramidal neuron dendrites modulate the summation of excitatory synaptic potentials4,5,6 and prevent the generation of dendritic calcium spikes7,8. Precisely timed somatic inhibition limits both the number of action potentials and the time window during which firing can occur8,9. The activity-dependent transcription factor NPAS4 regulates inhibitory synapse number and function in cell culture10, but how this transcription factor affects the inhibitory inputs that form on distinct domains of a neuron in vivo was unclear. Here we show that in the mouse hippocampus behaviourally driven expression of NPAS4 coordinatesthe redistribution of inhibitory synapses made onto a CA1 pyramidal neuron, simultaneously increasing inhibitory synapse number on the cell body while decreasing the number of inhibitory synapses on the apical dendrites. This rearrangement of inhibition is mediated in part by the NPAS4 target gene brain derived neurotrophic factor (Bdnf), which specifically regulates somatic, and not dendritic, inhibition. These findings indicate that sensory stimuli, by inducing NPAS4 and its target genes, differentially control spatial features of neuronal inhibition in a way that restricts the output of the neuron while creating a dendritic environment that is permissive for plasticity.

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Acknowledgements

We thank members of the Greenberg laboratory for comments, suggestions and critical reading of the manuscript. We thank A. Mardinly for observations and comments on NPAS4 protein induction, P. Greer and S. Flavell for observations and comments on Npas4 mRNA induction in response to enriched environment and B. Cruz Moreno for help with sectioning. We thank M. During for the gift of the AAV-Cre–GFP plasmid. GFP–gephyrin images were collected at the UCSD Neuroscience Microscopy Shared Facility sponsored by grant P30 NS047101. This work was funded by Helen Hay Whitney Foundation, L’Oreal USA Fellowship for Women in Science and The Medical Foundation/Charles A. King Trust Postdoctoral Fellowship (B.L.B.), NSF graduate student research fellowship (N.S.) and National Institutes of Health grant NS028829 (M.E.G.).

Author information

Author notes

    • Brenda L. Bloodgood
    •  & Nikhil Sharma

    These authors contributed equally to this work.

    • Heidi Adlman Browne
    •  & Alissa Z. Trepman

    Present addresses: Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA (H.A.B.); Department of Neuroscience, Brown University, National Institutes of Health Graduate Partnership Program, Providence, Rhode Island 02912, USA (A.T.).

Affiliations

  1. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Brenda L. Bloodgood
    • , Nikhil Sharma
    • , Heidi Adlman Browne
    • , Alissa Z. Trepman
    •  & Michael E. Greenberg
  2. Division of Biological Sciences, University of California San Diego, La Jolla, California 92093, USA

    • Brenda L. Bloodgood
  3. Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Nikhil Sharma

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Contributions

Experiments were designed by B.L.B., N.S. and M.E.G. Experiments were conducted and analysed by B.L.B., N.S., H.A.B. and A.Z.T. The manuscript was written by B.L.B., N.S. and M.E.G.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael E. Greenberg.

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https://doi.org/10.1038/nature12743

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