TY - JOUR T1 - New hippocampal neurons mature rapidly in response to ketamine but are not required for its acute antidepressant effects on neophagia in rats JF - eneuro JO - eneuro DO - 10.1523/ENEURO.0116-15.2016 SP - ENEURO.0116-15.2016 AU - Amelie Soumier AU - Rayna M. Carter AU - Timothy J. Schoenfeld AU - Heather A. Cameron Y1 - 2016/03/23 UR - http://www.eneuro.org/content/early/2016/03/23/ENEURO.0116-15.2016.abstract N2 - Virtually all antidepressants increase the birth of granule neurons in the adult dentate gyrus in rodents, providing a key basis for the neurogenesis hypothesis of antidepressant action. The novel antidepressant ketamine, however, shows antidepressant activity in humans within hours – far too rapid for a mechanism involving neuronal birth. Ketamine could potentially act more rapidly by enhancing maturation of new neurons born weeks earlier. To test this possibility, we assessed the effects of S-ketamine injection on maturation, as well as birth and survival, of new dentate gyrus granule neurons in rats, using the immediate-early gene zif268, PCNA, and BrdU respectively. We show that S-ketamine has rapid effects on new neurons, increasing the proportion of functionally-mature young granule neurons within 2 hours. A single injection of S-ketamine also increased cell proliferation and functional maturation, and decreased depressive-like behavior, for at least four weeks in rats treated with chronic corticosterone (a depression model) and controls. However, the behavioral effects of S-ketamine on neophagia were unaffected by elimination of adult neurogenesis. Together, these results indicate that ketamine has surprisingly rapid and long-lasting effects on recruitment of young neurons into hippocampal networks, but that ketamine has antidepressant-like effects that are independent of adult neurogenesis.Significance Statement: Ketamine is a novel antidepressant that works very rapidly. Although ketamine acts as an antagonist of NMDA-type glutamate receptors, it is not clear how or where in the brain it acts to produce its antidepressant effects. This study demonstrates that ketamine has very rapid effects on the maturation of hippocampal neurons born in the adult brain, which have been linked to depression. However, behavioral experiments showed antidepressant-like effects of ketamine on neophagia that are independent of new neurons, in contrast to the effects of classical antidepressants on this behavior. Ketamine effects on new neurons should be considered as potential side effects of treatment and also point to a role for NMDA receptors in the normal maturation of new neurons. ER -