A key requirement for synaptic Reelin signaling in ketamine-mediated behavioral and synaptic action

Proc Natl Acad Sci U S A. 2021 May 18;118(20):e2103079118. doi: 10.1073/pnas.2103079118.


Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant action in some patients with treatment-resistant depression. However, recent data suggest that ∼50% of patients with treatment-resistant depression do not respond to ketamine. The factors that contribute to the nonresponsiveness to ketamine's antidepressant action remain unclear. Recent studies have reported a role for secreted glycoprotein Reelin in regulating pre- and postsynaptic function, which suggests that Reelin may be involved in ketamine's antidepressant action, although the premise has not been tested. Here, we investigated whether the disruption of Reelin-mediated synaptic signaling alters ketamine-triggered synaptic plasticity and behavioral effects. To this end, we used mouse models with genetic deletion of Reelin or apolipoprotein E receptor 2 (Apoer2), as well as pharmacological inhibition of their downstream effectors, Src family kinases (SFKs) or phosphoinositide 3-kinase. We found that disruption of Reelin, Apoer2, or SFKs blocks ketamine-driven behavioral changes and synaptic plasticity in the hippocampal CA1 region. Although ketamine administration did not affect tyrosine phosphorylation of DAB1, an adaptor protein linked to downstream signaling of Reelin, disruption of Apoer2 or SFKs impaired baseline NMDA receptor-mediated neurotransmission. These results suggest that maintenance of baseline NMDA receptor function by Reelin signaling may be a key permissive factor required for ketamine's antidepressant effects. Taken together, our results suggest that impairments in Reelin-Apoer2-SFK pathway components may in part underlie nonresponsiveness to ketamine's antidepressant action.

Keywords: Apoer2; NMDA receptor; Reelin; antidepressant; ketamine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects*
  • Ketamine / pharmacology*
  • LDL-Receptor Related Proteins / physiology
  • Male
  • Mice
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / physiology
  • Phosphatidylinositol 3-Kinases / physiology
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Reelin Protein / physiology*
  • Signal Transduction / drug effects
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / physiology


  • Antidepressive Agents
  • LDL-Receptor Related Proteins
  • Receptors, N-Methyl-D-Aspartate
  • Reelin Protein
  • low density lipoprotein receptor-related protein 8
  • Ketamine
  • src-Family Kinases
  • Reln protein, mouse