NMDA 2A receptors in parvalbumin cells mediate sex-specific rapid ketamine response on cortical activity

Mol Psychiatry. 2019 Jun;24(6):828-838. doi: 10.1038/s41380-018-0341-9. Epub 2019 Jan 29.


Ketamine has emerged as a widespread treatment for a variety of psychiatric disorders when used at sub-anesthetic doses, but the neural mechanisms underlying its acute action remain unclear. Here, we identified NMDA receptors containing the 2A subunit (GluN2A) on parvalbumin (PV)-expressing inhibitory interneurons as a pivotal target of low-dose ketamine. Genetically deleting GluN2A receptors globally or selectively from PV interneurons abolished the rapid enhancement of visual cortical responses and gamma-band oscillations by ketamine. Moreover, during the follicular phase of the estrous cycle in female mice, the ketamine response was transiently attenuated along with a concomitant decrease of grin2A mRNA expression within PV interneurons. Thus, GluN2A receptors on PV interneurons mediate the immediate actions of low-dose ketamine treatment, and fluctuations in receptor expression across the estrous cycle may underlie sex-differences in drug efficacy.

Publication types

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

MeSH terms

  • Animals
  • Estrous Cycle / drug effects
  • Female
  • Interneurons / metabolism
  • Interneurons / physiology
  • Ketamine / metabolism*
  • Ketamine / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • N-Methylaspartate / metabolism
  • Parvalbumins / metabolism
  • Prefrontal Cortex / metabolism
  • Receptors, GABA-A / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Sex Factors


  • Parvalbumins
  • Receptors, GABA-A
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • Ketamine
  • N-methyl D-aspartate receptor subtype 2A