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TrkB dependent adult hippocampal progenitor differentiation mediates sustained ketamine antidepressant response

Author

Listed:
  • Zhenzhong Ma

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Tong Zang

    (University of Texas Southwestern Medical Center)

  • Shari G. Birnbaum

    (University of Texas Southwestern Medical Center)

  • Zilai Wang

    (University of Texas Southwestern Medical Center
    Memorial Sloan Kettering Cancer Center)

  • Jane E. Johnson

    (University of Texas Southwestern Medical Center)

  • Chun-Li Zhang

    (University of Texas Southwestern Medical Center)

  • Luis F. Parada

    (University of Texas Southwestern Medical Center
    Memorial Sloan Kettering Cancer Center)

Abstract

Adult neurogenesis persists in the rodent dentate gyrus and is stimulated by chronic treatment with conventional antidepressants through BDNF/TrkB signaling. Ketamine in low doses produces both rapid and sustained antidepressant effects in patients. Previous studies have shed light on post-transcriptional synaptic NMDAR mediated mechanisms underlying the acute effect, but how ketamine acts at the cellular level to sustain this anti-depressive function for prolonged periods remains unclear. Here we report that ketamine accelerates differentiation of doublecortin-positive adult hippocampal neural progenitors into functionally mature neurons. This process requires TrkB-dependent ERK pathway activation. Genetic ablation of TrkB in neural stem/progenitor cells, or pharmacologic disruption of ERK signaling, or inhibition of adult neurogenesis, each blocks the ketamine-induced behavioral responses. Conversely, enhanced ERK activity via Nf1 gene deletion extends the response and rescues both neurogenic and behavioral deficits in mice lacking TrkB. Thus, TrkB-dependent neuronal differentiation is involved in the sustained antidepressant effects of ketamine.

Suggested Citation

  • Zhenzhong Ma & Tong Zang & Shari G. Birnbaum & Zilai Wang & Jane E. Johnson & Chun-Li Zhang & Luis F. Parada, 2017. "TrkB dependent adult hippocampal progenitor differentiation mediates sustained ketamine antidepressant response," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01709-8
    DOI: 10.1038/s41467-017-01709-8
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    Cited by:

    1. Radhika Rawat & Elif Tunc-Ozcan & Tammy L. McGuire & Chian-Yu Peng & John A. Kessler, 2022. "Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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