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Ketamine Response Cycles in Females [Hensch Lab]

Ketamine Response Cycles in Females [Hensch Lab]

Ketamine for clinical use is clouded in controversy. Hallucinogenic party drug (“Special K”) and well-known anesthetic, it is increasingly touted as a panacea at low-doses for unresponsive depression or other cognitive disorders.

Not questioned is its rapid action. Hensch and colleagues recently elucidated a molecular cellular basis for its fast effects on brain activity using mutant mice. Neuronal firing was dramatically increased in the visual cortex of wildtype animals by low-dose ketamine injection.

However, this was not observed in mice lacking the 2A subunit of the N-methyl-D-aspartate (NMDA) glutamate receptor. Moreover, NMDA-2A gene deletion from a small subset of inhibitory neurons was sufficient to explain the rapid drug effects as a dis-inhibitory process. Surprisingly, NMDA-2A subunit synthesis in these cells was found to fluctuate in females in synch with their estrous state. This rendered them transiently insensitive to the drug.

Overall, these findings carry two important implications. First, the design and interpretation of clinical trials for low-dose ketamine use under conditions primarily affecting women, such as depression or Rett syndrome, need to be carefully evaluated. Second, a deeper understanding of the mechanisms of drug action might lead to improved therapeutics (e.g. cell-specific targeting of NMDA-2A receptors), potentially free of the addictive and other “dirty” side effects of ketamine.

by Takao Hensch

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Takao Hensch faculty profile, Hensch lab website

(l to r) Takao K. Hensch, Nathalie Picard, Anne E. Takesian, and Michela Fagiolini

(l to r) Takao K. Hensch, Nathalie Picard, Anne E. Takesian, and Michela Fagiolini