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 and Luis F. Parada ()
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Zhenzhong Ma: 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
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

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01709-8

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