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

• Published in: Molecular psychiatry Vol. 24; no. 6; pp. 828 - 838
• Main Authors: Picard, Nathalie, Takesian, Anne E., Fagiolini, Michela, Hensch, Takao K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2019; Nature Publishing Group
• Subjects: 14/32; 631/378; 64/60; 692/699/476/1414; 82/80; 9/30; 9/74; Animals; Behavioral Sciences; Biological Psychology; Care and treatment; Cortex; Estrous Cycle - drug effects; Estrus cycle; Female; Fourier transforms; Gene expression; Glutamic acid receptors (ionotropic); Immediate Communication; Interneurons; Interneurons - metabolism; Interneurons - physiology; Ketamine; Ketamine - metabolism; Ketamine - pharmacology; Male; Males; Medicine; Medicine & Public Health; Mental disorders; Mental illness; Mice; Mice, Inbred C57BL; N-Methyl-D-aspartic acid receptors; N-Methylaspartate - metabolism; Neurosciences; Oscillations; Parvalbumin; Parvalbumins - metabolism; Pharmacotherapy; Prefrontal Cortex - metabolism; Psychiatry; Receptors, GABA-A - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Receptors, N-Methyl-D-Aspartate - physiology; Sex Factors; Variation
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-018-0341-9

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.