Potential link between antidepressant-like effects of ketamine and promotion of adult neurogenesis in the ventral hippocampus of mice.

A single dose of ketamine promotes the growth of new neurons (neurogenesis) specifically in the ventral hippocampus, the region linked to emotion, but not in the dorsal hippocampus, which is associated with spatial memory, in adult mice. Ketamine increased densities of neuronal progenitors and newborn granule cells and sped their maturation only in the ventral hippocampus. It did not affect spatial memory but reduced depression-related behavior. The ventral hippocampus showed higher baseline levels of the GluN2B subunit of the NMDAR, and ketamine induced greater expression there of GluN2B, phosphorylated mTOR, the GluA1 subunit of AMPAR, and BDNF. These ventral-dominant molecular changes may underlie ketamine's antidepressant-like effects.

Study at a glance

Abstract

Recent studies have shown that ketamine, an open channel blocker of the N-methyl-d-aspartate receptor (NMDAR), is effective for patients with treatment-resistant depression. In this study, we aimed to elucidate the potential link between antidepressant-like effects of a single ketamine administration and dorsoventral differentiation in adult hippocampal neurogenesis. Immunohistochemical analyses revealed that elevation in the densities of neuronal progenitors and newborn granule cells by ketamine was seen in the ventral (related to emotion), but not dorsal (related to spatial memory), hippocampus in adult mice, although the densities of neural stem cells were not affected by ketamine in both the dorsal and ventral regions. Promotion of maturation of newborn granule cells by ketamine was evident in the ventral, but not dorsal, hippocampus. Behavioral analyses showed that ketamine did not affect spatial memory but ameliorated depression-related behavior. Western blot analyses showed that the basal expression of the GluN2B, but not GluN1, subunit of the NMDAR was higher in the ventral hippocampus than in the dorsal hippocampus. The induction of expression of GluN2B subunit of the NMDAR, phosphorylated mammalian target of rapamycin (p-mTOR), GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), and brain derived neurotrophic factor (BDNF), by ketamine was greater in the ventral hippocampus than in the dorsal hippocampus. Our results demonstrate that a single ketamine administration promotes adult neurogenesis in the ventral hippocampus quite selectively. Furthermore, ventral-dominant induction of the GluN2B subunit of NMDAR, p-mTOR, GluA1 subunit of AMPAR, and BDNF, in the hippocampus may underlie the unique antidepressant-like effects of ketamine.