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. 2016 Mar 31;3(2):ENEURO.0116-15.2016.
doi: 10.1523/ENEURO.0116-15.2016. eCollection 2016 Mar-Apr.

New Hippocampal Neurons Mature Rapidly in Response to Ketamine But Are Not Required for Its Acute Antidepressant Effects on Neophagia in Rats

Amelie Soumier  1 , Rayna M Carter  1 , Timothy J Schoenfeld  1 , Heather A Cameron  1
Affiliations

New Hippocampal Neurons Mature Rapidly in Response to Ketamine But Are Not Required for Its Acute Antidepressant Effects on Neophagia in Rats

Amelie Soumier et al. eNeuro. .

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.

Keywords: antidepressive agents; cell proliferation; dentate gyrus; mood disorders; neurogenesis; neuronal maturation.

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Figures

Figure 1.
Figure 1.
Rapid and sustained behavioral effects of S-ketamine. A, Short-term S-ketamine (ket) treatment reduced the latency to eat in the novelty-suppressed feeding test (one-way ANOVA, F(3,14) = 6.61, p = 0.005; *Holm–Sidak test, 10 mg/ml vs saline, p = 0.004). B, In the repeated forced swim test, short-term administration of S-ketamine reduced the time spent immobile immediately and 21 d later, while fluoxetine had no effect (two-way repeated-measures ANOVA; treatment effect: F(2,9) = 31.65, p = 0.0001; time effect: F(1,9) = 31.47, p = 0.0003; treatment × time interaction: F(2,9) = 0.002, p =0.99; ***p < 0.001 vs saline in post hoc test). All bars represent mean ± standard error of the mean (SEM).
Figure 2.
Figure 2.
Examples of immunohistochemical markers. A, After kainate injection, all mature granule neurons and some BrdU-labeled 16-d-old NeuN+ neurons expressed zif268, indicating synaptic activation. GCL, granule cell layer B, Dividing cells (arrows) were identified using PCNA immunohistochemistry. C, Cells surviving 2-3 weeks (arrows) were identified with BrdU immunohistochemistry (gray-brown); immunonegative cells were stained with blue-purple counterstain.
Figure 3.
Figure 3.
Rapid effects of ketamine on granule cell maturation and proliferation. A, S-ketamine (ket) increased the proportion of 16-d-old BrdU+ cells colabeled with NeuN and zif268 (zif) 16 h later, relative to saline-treated controls (sal) (*t test, t(4) = 3.065, p =0.0375). All bars represent mean ± SEM. B, S-ketamine increased the number of PCNA+ (dividing) cells in the subgranular zone 16 h later (*t test, t(10) = 2.42, p = 0.0359). C, Animal treatment time course for short-term effects; ketamine injection was 10 mg/kg, i.p., in each experiment. D, The maturation effect was not seen in 7-d-old cells (t test, t(9) = 0.98, p = 0.35). E, Animal treatment time course for short-term effects in young cells. F, G, Increased zif/NeuN coexpression and strong NeuN expression were seen in 14-d-old cells within 2 h of ketamine treatment (zif: *t test, t(9) = 2.33, p = 0.0450; strong NeuN: *t test, t(9) = 3.55, p = 0.0062). H, Animal treatment time course for very rapid effects on maturation.
Figure 4.
Figure 4.
Effects of long-term ketamine treatment. A, B, Animal treatment time courses; all ketamine injections were 10 mg/kg, i.p. C, D, Long-term daily ketamine treatment for 14 d (C) or 21 d (D) increased the proportion of zif/NeuN+ BrdU+ granule cells (*14 d: t test, t(9) = 3.20, p = 0.0108; *21 d: t test, t(11) = 2.773, p = 0.0181). E, F, S-ketamine had no effect on cell proliferation when administered daily for 14 or 21 d (14 d: t(10) = 0.035, p = 0.973; 21 d: t(9) = 0.955, p = 0.365). G, H, BrdU+ cell survival was unaffected by 14 d of daily treatment with S-ketamine (t test, t(10) = 1.03, p = 0.33) but was decreased after 21 d (*t test, t(12) = 2.71, p = 0.0191). All bars represent the mean ± SEM (n = 6-7 per group).
Figure 5.
Figure 5.
Sustained effects of S-ketamine in a depression model. A, Ketamine given 32 d earlier increased zif/NeuN expression in 16-d-old cells regardless of long-term corticosterone exposure (main effect of CORT: F(1,17) = 0.00, p = 0.996; *main effect of ketamine: F(1,17) = 14.99, p = 0.0017; CORT × ketamine interaction: F(1,17) = 0.0005, p = 0.9821 by two-way ANOVA). B, S-ketamine increased the number of PCNA+ cells 32 d later and prevented the inhibition of proliferation by long-term corticosterone treatment (*main effect of ketamine: F(1, 23) = 7.44, p = 0.013; *main effect of CORT: F(1,23) = 8.35, p = 0.009; CORT × ketamine interaction: F(1,23) = 0.00, p = 0.988 by two-way ANOVA). C, Animal treatment time course for maturation and proliferation effects. D, A single S-ketamine injection prior to long-term CORT treatment prevented a decrease in sucrose preference (one-way ANOVA, F(2,15) = 6.98, p = 0.0072; *p < 0.05 vs saline in post hoc test). Values represent the mean ± SEM (n = 4-6 per group). E, Neither long-term exposure to CORT nor short-term ketamine exposure prior to CORT significantly altered new cell survival (F(2,15) = 1.12, p = 0.35 by one-way ANOVA). Values represent the mean ± SEM (n = 6-7 per group. F, Animal treatment time course for sucrose preference and survival effects.
Figure 6.
Figure 6.
Neurogenesis is not required for the S-ketamine effect on novelty-suppressed feeding. A, Animal treatment time course showing valganciclovir to inhibit neurogenesis, the injection of saline (sal) or ketamine (ket; 10 mg/kg), and NSF testing. B, Photographs show DCX-expressing young granule neurons (green) in the dentate gyrus of valganciclovir (VGCV)-treated wild-type rats (WT), but not in GFAP-TK (TK) rats. Blue counterstain shows cell nuclei. C, Higher magnification of granule cell layer showing DCX staining. D, Quantification shows near-complete absence of DCX+ new neurons in GFAP-TK rats and no effect of short-term S-ketamine treatment on DCX+ cell number. (*main effect of genotype: F(1,20) = 183.6, p < 0.0001; main effect of ketamine: F(1,20) = 1.471, p = 0.2392; genotype × ketamine interaction: F(1,20) = 1.418, p = 0.2477, all by two-way ANOVA) E, In the NSF test, the latency to eat in a novel arena was decreased by S-ketamine in both wild-type and GFAP-TK rats (*main effect of genotype: F(1,20) = 0.2827, p = 0.6008; main effect of ketamine: F(1,20) = 13.24, p = 0.0016; genotype × ketamine interaction: F(1,20) = 0.3756, p = 0.5469, all by two-way ANOVA). All bars represent mean ± SEM.
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