TrkB dependent adult hippocampal progenitor differentiation mediates sustained ketamine antidepressant response

Zhenzhong Ma, Tong Zang, Shari G. Birnbaum, Zilai Wang, Jane E. Johnson, Chun Li Zhang, Luis F. Parada

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1668
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Ketamine
Antidepressive Agents
Neurogenesis
rodents
deletion
stem cells
neurons
genes
Neurofibromatosis 1 Genes
ablation
mice
activation
Neural Stem Cells
MAP Kinase Signaling System
Brain-Derived Neurotrophic Factor
Dentate Gyrus
Gene Deletion
dosage
Ablation
Stem cells

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

TrkB dependent adult hippocampal progenitor differentiation mediates sustained ketamine antidepressant response. / Ma, Zhenzhong; Zang, Tong; Birnbaum, Shari G.; Wang, Zilai; Johnson, Jane E.; Zhang, Chun Li; Parada, Luis F.

In: Nature Communications, Vol. 8, No. 1, 1668, 01.12.2017.

Research output: Contribution to journalArticle

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