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Neurofilament subunits are integral components of synapses and modulate neurotransmission and behavior in vivo

Molecular Psychiatry volume 20, pages 986–994 (2015)Cite this article

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Abstract

Synaptic roles for neurofilament (NF) proteins have rarely been considered. Here, we establish all four NF subunits as integral resident proteins of synapses. Compared with the population in axons, NF subunits isolated from synapses have distinctive stoichiometry and phosphorylation state, and respond differently to perturbations in vivo. Completely eliminating NF proteins from brain by genetically deleting three subunits (α-internexin, NFH and NFL) markedly depresses hippocampal long-term potentiation induction without detectably altering synapse morphology. Deletion of NFM in mice, but not the deletion of any other NF subunit, amplifies dopamine D1-receptor-mediated motor responses to cocaine while redistributing postsynaptic D1-receptors from endosomes to plasma membrane, consistent with a specific modulatory role of NFM in D1-receptor recycling. These results identify a distinct pool of synaptic NF subunits and establish their key role in neurotransmission in vivo, suggesting potential novel influences of NF proteins in psychiatric as well as neurological states.

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Acknowledgements

We thank Corrine Peterhoff for assistance with figures and Nicole Gogel for manuscript preparation. This work was supported by Grant 5R01AG005604 (RAN) from the National Institutes on Aging. BSB is supported by NIH grant (R01 AA019443).

Author Contributions

AY, HS, V, BSB and RAN designed the research; AY, HS, V, BSB, AK, AH, MB, J-HL and YS performed the research; AY, HS, V, BSB, MB, AK, AH, MVR, VD, J-PJ and RAN analyzed the data; PSM provided reagents; VM-YL provided reagents and critical advice; AY, HS and RAN wrote the paper.

Author information

Author notes

  1. Y Sato

    Present address: 10Current address: Laboratory of Molecular Neuroscience, Department of Biological Sciences, Tokyo Metropolitan University, Building 9, 4th Floor, Room 493, 1-1 Minami-osawa, Hachioji, Tokyo 192-0397, Japan.,

  2. A Yuan, H Sershen and Veeranna: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA

    A Yuan,  Veeranna, A Kumar, M Berg, J-H Lee, Y Sato, M V Rao, P S Mohan, V Dyakin & R A Nixon

  2. Department of Psychiatry, New York University School of Medicine, New York, NY, USA

    A Yuan, H Sershen,  Veeranna, A Kumar, J-H Lee, M V Rao & R A Nixon

  3. Neurochemistry Division, Nathan Kline Institute, Orangeburg, NY, USA

    H Sershen & A Hashim

  4. Analytical Psychopharmacology Division, Nathan Kline Institute, Orangeburg, NY, USA

    B S Basavarajappa

  5. Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY, USA

    B S Basavarajappa

  6. Département d'anatomie et physiologie de l'Université Laval, Centre de Recherche du Centre Hospitalier de l'Université Laval, Québec, QC, Canada

    J-P Julien

  7. Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    V M-Y Lee

  8. Department of Cell Biology, New York University School of Medicine, New York, NY, USA

    R A Nixon

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Correspondence to A Yuan or R A Nixon.

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Yuan, A., Sershen, H., Veeranna et al. Neurofilament subunits are integral components of synapses and modulate neurotransmission and behavior in vivo. Mol Psychiatry 20, 986–994 (2015). https://doi.org/10.1038/mp.2015.45

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