title: New Hippocampal Neurons Mature Rapidly in Response to Ketamine But Are Not Required for Its Acute Antidepressant Effects on Neophagia in Rats.
abstract: Virtually all antidepressant agents 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 (S-(+)-ketamine hydrochloride) injection on maturation, as well as birth and survival, of new dentate gyrus granule neurons in rats, using the immediate-early gene zif268, proliferating cell nuclear antigen, 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 h. A single injection of S-ketamine also increased cell proliferation and functional maturation, and decreased depressive-like behavior, for at least 4 weeks in rats treated with long-term corticosterone administration (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 the recruitment of young neurons into hippocampal networks, but that ketamine has antidepressant-like effects that are independent of adult neurogenesis.
authors.affiliation: Section on Neuroplasticity, National Institute of Mental Health, National Institutes of Health , Bethesda, Maryland 20892.
authors.forename: Amelie
authors.initials: A
authors.lastname: Soumier
authors.affiliation: Section on Neuroplasticity, National Institute of Mental Health, National Institutes of Health , Bethesda, Maryland 20892.
authors.forename: Rayna M
authors.initials: RM
authors.lastname: Carter
authors.affiliation: Section on Neuroplasticity, National Institute of Mental Health, National Institutes of Health , Bethesda, Maryland 20892.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Schoenfeld
authors.affiliation: Section on Neuroplasticity, National Institute of Mental Health, National Institutes of Health , Bethesda, Maryland 20892.
authors.forename: Heather A
authors.identifier: 0000-0002-3245-5777
authors.initials: HA
authors.lastname: Cameron
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003345:Corticosterone / Q000008:administration & dosage; D003863:Depression / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005508:Food Deprivation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D020318:Rats, Long-Evans; D055647:Rats, Transgenic; D013550:Swimming / Q000523:psychology; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D007649:Ketamine; D003345:Corticosterone
keywords: antidepressive agents; cell proliferation; dentate gyrus; mood disorders; neurogenesis; neuronal maturation