Ketamine Rapidly Enhances Glutamate-Evoked Dendritic Spinogenesis in Medial Prefrontal Cortex Through Dopaminergic Mechanisms

Mingzheng Wu, Samuel Minkowicz, Vasin Dumrongprechachan, Pauline Hamilton, Yevgenia Kozorovitskiy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


Background: Ketamine elicits rapid onset antidepressant effects in patients with clinical depression through mechanisms hypothesized to involve the genesis of neocortical dendritic spines and synapses. Yet, the observed changes in dendritic spine morphology usually emerge well after ketamine clearance, raising questions about the link between rapid behavioral effects of ketamine and plasticity. Methods: Here, we used two-photon glutamate uncaging/imaging to focally induce spinogenesis in the medial prefrontal cortex, directly interrogating baseline and ketamine-associated plasticity of deep layer pyramidal neurons in C57BL/6 mice. We combined pharmacological, genetic, optogenetic, and chemogenetic manipulations to interrogate dopaminergic mechanisms underlying ketamine-induced rapid enhancement in evoked plasticity and associated behavioral changes. Results: We found that ketamine rapidly enhances glutamate-evoked spinogenesis in the medial prefrontal cortex, with timing that matches the onset of its behavioral efficacy and precedes changes in dendritic spine density. Ketamine increases evoked cortical spinogenesis through dopamine Drd1 receptor (Drd1) activation that requires dopamine release, compensating blunted plasticity in a learned helplessness paradigm. The enhancement in evoked spinogenesis after Drd1 activation or ketamine treatment depends on postsynaptic protein kinase A activity. Furthermore, ketamine's behavioral effects are blocked by chemogenetic inhibition of dopamine release and mimicked by activating presynaptic dopaminergic terminals or postsynaptic Gαs-coupled cascades in the medial prefrontal cortex. Conclusions: Our findings highlight dopaminergic mediation of rapid enhancement in activity-dependent dendritic spinogenesis and behavioral effects induced by ketamine.

Original languageEnglish (US)
Pages (from-to)1096-1105
Number of pages10
JournalBiological psychiatry
Issue number11
StatePublished - Jun 1 2021


  • 2-Photon glutamate uncaging
  • Dendritic spine
  • Dopamine
  • Ketamine
  • Medial prefrontal cortex
  • Spinogenesis

ASJC Scopus subject areas

  • Biological Psychiatry


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