Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice

doi:10.1038/s41467-022-30386-5

. 2022 May 12;13(1):2650.

doi: 10.1038/s41467-022-30386-5.

Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice

Radhika Rawat¹, Elif Tunc-Ozcan², Tammy L McGuire², Chian-Yu Peng², John A Kessler²

Affiliations

¹ Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. radhika.rawat@northwestern.edu.
² Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

PMID: 35551462
PMCID: PMC9098911
DOI: 10.1038/s41467-022-30386-5

Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice

Radhika Rawat et al. Nat Commun. 2022.

. 2022 May 12;13(1):2650.

doi: 10.1038/s41467-022-30386-5.

Authors

Radhika Rawat¹, Elif Tunc-Ozcan², Tammy L McGuire², Chian-Yu Peng², John A Kessler²

Affiliations

¹ Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA. radhika.rawat@northwestern.edu.
² Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.

PMID: 35551462
PMCID: PMC9098911
DOI: 10.1038/s41467-022-30386-5

Abstract

Ketamine treatment decreases depressive symptoms within hours, but the mechanisms mediating these rapid antidepressant effects are unclear. Here, we demonstrate that activity of adult-born immature granule neurons (ABINs) in the mouse hippocampal dentate gyrus is both necessary and sufficient for the rapid antidepressant effects of ketamine. Ketamine treatment activates ABINs in parallel with its behavioral effects in both stressed and unstressed mice. Chemogenetic inhibition of ABIN activity blocks the antidepressant effects of ketamine, indicating that this activity is necessary for the behavioral effects. Conversely, chemogenetic activation of ABINs without any change in neuron numbers mimics both the cellular and the behavioral effects of ketamine, indicating that increased activity of ABINs is sufficient for rapid antidepressant effects. These findings thus identify a specific cell population that mediates the antidepressant actions of ketamine, indicating that ABINs can potentially be targeted to limit ketamine's side effects while preserving its therapeutic efficacy.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Ketamine treatment increases the activity of immature DG neurons.**
a Experimental timeline. Saline or ketamine was administered by intraperitoneal (i.p.) injection to wild-type C57BL/6 mice 24 h prior to behavioral testing. Immediately following testing, mice were euthanized for sample collection. b Sociability Ratio. Student’s t-test: saline (n = 19) vs ketamine (n = 19) ***p = 0.0009. c Novelty Ratio. Saline (n = 19) vs ketamine (n = 19) ****p < 0.0001 by Welch’s t-test. d Time immobile in seconds. Student’s t-test: Saline (n = 19) vs ketamine (n = 19) ****p < 0.0001). e–g Representative immunohistochemical (IHC) staining of cFOS⁺ (magenta) cells in the dentate gyrus (DG) and quantification of cFOS⁺ cells/mm³ (n = 4 mice/group) **p = 0.0096 by Student’s t-test. h Quantification of EGR1⁺ cells/mm³. saline (n = 4) vs ketamine (n = 4) ***p < 0.0001 by Student’s t-test. i, j Representative IHC staining of NeuN⁺ (green), Egr1⁺ (red, outlined arrow), and double-positive (yellow, solid white arrow) cells in the DG. k Quantification of EGR1⁺NeuN⁺ cells and EGR1⁺NeuN⁻ cells in saline-treated and ketamine-treated mouse DGs (n = 4 mice/group). Two-way ANOVA: NeuN F_{1, 12} = 205.0 ****p < 0.0001, ketamine F_{1, 12} = 60.95 ****p < 0.0001; NeuN*ketamine F_1,12 = 50.20 ****p < 0.0001; Tukey’s post hoc test: saline NeuN⁺ vs saline NeuN⁻ **p = 0.0013, saline NeuN⁺ vs ketamine NeuN⁺ ****p < 0.0001, saline NeuN⁺ vs ketamine NeuN⁻ **p = 0.0029, saline NeuN⁻ vs ketamine NeuN⁺ ****p < 0.0001, saline NeuN⁻ vs ketamine NeuN⁻ not significant (ns) p = 0.955, ketamine NeuN⁺ vs ketamine NeuN⁻ ****p < 0.0001). l, m Representative IHC staining of EGR1⁺ (magenta, white asterisk), Calbindin (Calb)⁺ (green), and double-positive (pink) cells in the DG. n Quantification of EGR1⁺Calb⁻ cells and EGR1⁺Calb⁺ cells in saline-treated and ketamine-treated mouse DGs (n = 4 mice/group). Two-way ANOVA: Calb F_{1, 12} = 15.08 **p = 0.0022, ketamine F_{1, 12} = 115.1 ****p < 0.001, Calb*ketamine F_{1, 12} = 66.96 ****p < 0.0001; Tukey’s post hoc test: saline Calb⁻ vs ketamine Calb⁻ ****p < 0.0001, saline Calb⁻ vs saline Calb⁺ *p = 0.0442, saline Calb⁻ vs Calb⁺ ketamine **p = 0.002, ketamine Calb⁻ vs saline Calb⁺ ****p < 0.0001, ketamine Calb⁻ vs ketamine Calb⁺ ****p < 0.0001, saline Calb⁺ vs ketamine Calb⁺ ns p = 0.3192. o, p Representative IHC staining of EGR1⁺ (red) and Calretinin (CR)⁺ (green) cells in the DG. White arrows depict example double-positive cells. q Quantification of EGR1⁺CR⁻ cells and EGR1⁺CR⁺ cells in saline-treated and ketamine-treated mouse DGs (n = 4 mice/group). Two-way RM ANOVA: CR F_1,6 = 0.1254 ns p = 0.7353; ketamine F_1,6 = 19.10 **p = 0.0047; Sidak’s multiple comparisons test: saline CR⁻ vs ketamine CR⁻ ns p = 0.5193, saline CR⁺ vs ketamine CR⁺ ****p < 0.0001. Data were presented as means ± s.e.m. Each replicate is a different mouse. Source data and complete statistics are provided as a source data file. Scale bars 50 μm.

**Fig. 2. Selectively silencing adult-born immature granule neurons (ABINs) blocks the acute effects of ketamine.**
a Experimental timeline. Ascl1-Cre;hM4Di mice received once-daily tamoxifen injections for 5 days. Three weeks after the first tamoxifen dose, CNO or vehicle was administered by intraperitoneal injection (i.p.) and 2 h later, mice were given an i.p. injection of saline or ketamine. Either CNO or vehicle was provided ad libitum overnight. Twenty-four hours after saline or ketamine treatment, mice underwent behavioral testing and euthanasia immediately afterward for sample collection. b Sociability Ratio. Two-way ANOVA: CNO*ketamine F_{1, 34} = 11.09 **p = 0.0021, CNO F_1,34 = 11.12 **p = 0.0021, ketamine F_1,34 = 36.45 ****p < 0.0001; Tukey’s post hoc test: vehicle + saline (n = 9) vs vehicle + ketamine (n = 10) ****p < 0.0001, vehicle + ketamine vs CNO + saline (n = 9) ****p < 0.0001, vehicle + ketamine vs CNO + ketamine (n = 10) ***p = 0.0002, vehicle + saline vs CNO + saline ns p > 0.9999, vehicle + saline vs CNO + ketamine ns p = 0.2425, CNO + saline vs CNO + ketamine ns p = 0.2413. c Novelty Ratio. Two-way ANOVA: CNO*ketamine F_{1, 36} = 16.62 ***p = 0.0002, CNO F_{1, 36} = 25.63 ****p < 0.0001, ketamine F_{1, 36} = 3.047 ns p = 0.0894; Tukey’s post hoc test: vehicle+saline (n = 10) vs. vehicle + ketamine (n = 12) ***p = 0.0006, vehicle + ketamine vs. CNO + saline (n = 10) ****p < 0.0001, vehicle + ketamine vs. CNO + ketamine (n = 8) ****p < 0.0001, vehicle + saline vs. CNO + saline ns p = 0.8948,vehicle + saline vs. CNO + ketamine ns p = 0.1334, CNO + saline vs. CNO + ketamine ns p = 0.4078. d Time immobile in seconds. Two-way ANOVA: CNO F_{1, 60} = 12.93, ***p = 0.0007; ketamine F_1,60 = ns p = 0.1060; CNO*ketamine F_1,60 = 13.65, ***p = 0.0005. Tukey’s post hoc test: vehicle + saline(n = 18) vs vehicle + ketamine (n = 19) ***p = 0.0007; vehicle + saline vs CNO + saline (n = 12) ns p = 0.999; vehicle + saline vs CNO + ketamine (n = 15) ns p = 0.4919; vehicle + ketamine vs CNO + saline **p = 0.0034; vehicle + ketamine vs CNO + ketamine ****p < 0.0001; CNO + saline vs CNO + ketamine ns p = 0.53. e Distance traveled in centimeters (vehicle + saline n = 10, vehicle + ketamine n = 12, CNO + saline n = 11, CNO + ketamine n = 7). Two-way ANOVA ns. f Quantification of HA⁺ cells/mm³ in the DG (n = 4 mice/group). Two-way ANOVA ns. g Quantification of HA⁺EGR1⁺ cells/mm³. Two-way ANOVA: CNO F_1,12 = 157.3 ***p < 0.0001, ketamine F_1,12 = 61.26 ****p < 0.0001, CNO*ketamine F_1,12 = 58.56 ****p = 0.0001; Tukey’s post hoc test: vehicle + saline vs vehicle + ketamine ****p < 0.0001, vehicle + saline vs CNO + saline *p = 0.0213, vehicle + saline vs CNO + ketamine *p = 0.0265, vehicle + ketamine vs CNO + saline ****p < 0.0001, vehicle + ketamine vs CNO + ketamine ****p < 0.0001, CNO + saline vs CNO + ketamine ns p = 0.9993. h Quantification of EGR1⁺ cells/mm³ (n = 4 mice/group). Two-way ANOVA: CNO*ketamine F_1,14 = 28.83 p < 0.0001, CNO F_{1, 14} = 11.09 **p = 0.0050, ketamine F_{1, 14} = 17.03 **p = 0.0010; Tukey’s post hoc test: vehicle + saline vs vehicle + ketamine ****p < 0.0001, vehicle + ketamine vs CNO + saline ***p = 0.0006, vehicle + ketamine vs CNO + ketamine ***p = 0.0001, CNO + saline vs CNO + ketamine ns p = 0.8376, vehicle + saline vs CNO + saline ns p = 0.4957, vehicle + saline vs CNO + ketamine ns p = 0.9414. i–m Representative IHC of EGR1⁺ (magenta, nuclear) and HA⁺ (green, cytoplasmic) colocalization. White arrows indicate colocalized cells. Data were presented as means ± s.e.m. Each replicate is a different mouse. Source data and complete statistics are provided as a source data file. Scale bars 50 μm.

**Fig. 3. Selectively silencing ABINs blocks ketamine’s ability to rescue stress-induced behavioral phenotypes.**
a Experimental timeline. Ascl1-Cre;hM4Di mice received once-daily tamoxifen injections for 5 days. On day 7, a 3-week paradigm of unpredictable mild chronic stress (UCMS) was started. CNO or vehicle then was administered by intraperitoneal injection (i.p.) and 2 h later, mice were given an i.p. injection of saline or ketamine. Either CNO or vehicle was provided ad libitum *overnight*. 24 h after saline or ketamine treatment, mice underwent behavioral testing and euthanasia immediately afterward for sample collection. b Sociability Ratio. Two-way ANOVA: Interaction F_{1, 48} = 12.76 ***p = 0.0008, CNO F_{1, 48} = 16.88 ***p = 0.0002, ketamine F_{1, 48} = 6.716 *p = 0.0126; Tukey’s post hoc test: vehicle + saline (n = 14) vs vehicle + ketamine (n = 15) ***p = 0.0001, vehicle + ketamine vs CNO + saline (n = 10) ***p = 0.0002, vehicle + ketamine vs CNO + ketamine (n = 13) ****p < 0.0001, vehicle + saline vs CNO + saline ns p = 0.9833, vehicle + saline vs CNO + ketamine ns p = 0.6882, CNO + saline vs CNO + ketamine ns p = 0.9137. c Novelty Ratio. Two-way ANOVA: Interaction F_{1, 50} = 19.73 ****p < 0.0001, CNO F_1,50 = 28.00 ****p < 0.0001, ketamine ***F_{1, 50} = 13.81 p = 0.0005; Tukey’s post hoc test: vehicle + saline (n = 15) vs vehicle + ketamine (n = 16) ****p < 0.0001, vehicle + saline vs CNO + saline (n = 10) ns p = 0.9389, vehicle + saline vs CNO + ketamine (n = 13) ns p = 0.6606, vehicle + ketamine vs CNO + saline ****p < 0.0001, vehicle + ketamine vs CNO + ketamine ****p < 0.0001, CNO + saline vs CNO + ketamine ns p = 0.9637. d Time immobile in seconds. Two-way ANOVA: Interaction F_{1, 60} = 9.515 **p = 0.0031, CNO F_{1, 60} = 1.813 p = 0.1832, ketamine F_{1, 60} = 17.45 ****p < 0.0001; Tukey’s post hoc test: vehicle + saline (n = 15) vs vehicle + ketamine (n = 17) ****p < 0.0001, vehicle + ketamine vs CNO + saline (n = 13) **p = 0.002, vehicle + ketamine vs CNO + ketamine (n = 19) **p = 0.0074, vehicle + saline vs CNO + saline ns p = 0.6552, vehicle + saline vs CNO + ketamine ns p = 0.1749, CNO + saline vs CNO + ketamine ns p = 0.8692. e Distance traveled in centimeters (vehicle + saline n = 11, vehicle+ketamine n = 15, CNO + saline n = 11, CNO + ketamine n = 12). Two-way ANOVA: ns. f Quantification of HA⁺ cells/mm³ in the DG (n = 4 mice/group). Two-way ANOVA: ns. g Quantification of HA⁺EGR1⁺ cells/mm³ (n = 4 mice/group). Two-way ANOVA: Interaction F_{1, 11} = 11.65 **p = 0.0058, CNO F_{1, 11} = 16.35 **p = 0.0019, Antidepressant F_{1, 11} = 5.861 *p = 0.0339; Tukey’s post hoc test: vehicle + saline vs vehicle + ketamine **p = 0.01, vehicle + saline vs CNO + saline ns p = 0.9721, vehicle + saline vs CNO + ketamine ns p = 0.6936, vehicle + ketamine vs CNO + saline **p = 0.0028, vehicle + ketamine vs CNO + ketamine ***p = 0.0009, CNO + saline vs CNO + ketamine ns p = 0.883. h EGR1⁺ cells/mm³ (n = 4 mice/group). Two-way ANOVA: ns. i–m Representative IHC of EGR1⁺ (magenta) and HA⁺ (green) staining. Data were presented as means ± s.e.m and were analyzed by t-test or ANOVA and Tukey’s post hoc test. Each replicate is a different mouse. Source data and complete statistics are provided as a source data file. Scale bars 50 μm.

**Fig. 4. Ketamine’s effects on ABINs and mouse behavior require AMPA receptors.**
a Experimental timeline. Wild-type C57BL/6 mice received two injections 24 h prior to behavioral testing: either saline or ketamine by intraperitoneal (i.p.) injection and either NBQX or vehicle (vehicle) by subcutaneous injection. Immediately following testing, mice were euthanized for sample collection. b Sociability Ratio. Two-way ANOVA: Interaction F_{1, 30} = 4.514 *p = 0.0420, NBQX F_{1, 30} = 10.98 **p = 0.0024, ketamine F_{1, 30} = 9.107 **p = 0.0052; Tukey’s post hoc test: vehicle + saline vs vehicle + ketamine **p = 0.007, vehicle + ketamine (n = 9) vs NBQX + saline (n = 10) ***p = 0.0003, vehicle + ketamine vs NBQX + ketamine (n = 8) **p = 0.0029, NBQX + saline vs NBQX + ketamine ns p = 0.9142, vehicle + saline (n = 7) vs NBQX + saline ns p = 0.8377, vehicle + saline vs NBQX + ketamine ns p = 0.9972. c Novelty Ratio. Two-way ANOVA: Interaction F_{1, 30} = 6.101 *p = 0.0194, NBQX F_{1, 30} = 4.520 *p = 0.0418, ketamine F_{1, 30} = 4.717 *p = 0.0379; Tukey’s post hoc test: vehicle + saline (n = 9) vs vehicle + ketamine (n = 8) *p = 0.0132, vehicle + ketamine vs NBQX + saline (n = 9) *p = 0.0239, vehicle + ketamine vs NBQX + ketamine (n = 8) *p = 0.0179, NBQX + saline vs NBQX + ketamine ns p = 0.9966, vehicle + saline vs NBQX + saline ns p = 0.9943, vehicle + saline vs NBQX + ketamine ns >0.9999. d Time immobile in seconds. Two-way ANOVA: Interaction F_{1, 36} = 9.580 **p = 0.0038, CNO F_1,36 = 6.074 *p = 0.0186, ketamine F_{1, 36} = 7.328 *p = 0.0103; Tukey’s post hoc test: vehicle + saline (n = 10) vs vehicle + ketamine (n = 10) **p = 0.0012, vehicle + ketamine vs NBQX + saline (n = 10) **p = 0.0043, vehicle + ketamine vs NBQX + ketamine (n = 10) **p = 0.002, vehicle + saline vs NBQX + saline ns p = 0.97, vehicle + saline vs NBQX + ketamine ns p = 0.9982, NBQX + saline vs NBQX + ketamine ns p = 0.9927. e Quantification of EGR1⁺Calb^– single-positive cells (n = 3 mice/group). Two-way ANOVA: Interaction F_{1, 8} = 106.7 ****p < 0.0001, NBQX F_{1, 8} = 88.58 ****p < 0.0001, ketamine F_{1, 8} = 88.93 ****p < 0.0001; Tukey’s post hoc test: vehicle + saline vs vehicle + ketamine ****p < 0.0001, vehicle + saline vs NBQX + saline ns p = 0.9128, vehicle + saline vs NBQX + ketamine ns >0.9999, vehicle + ketamine vs NBQX + saline ****p < 0.0001, vehicle + ketamine vs NBQX + ketamine ****p < 0.0001, NBQX + saline vs NBQX + ketamine ns p = 0.9173. f–i Representative IHC staining of EGR1⁺ (red) single-positive cells (indicated by a white arrow), Calb⁺ (green) cells, and double-positive (yellow) cells in the DG. Data are presented as means ± s.e.m. Each replicate is a different mouse. Source data and complete statistics are provided as a source data file. Scale bars 50 μm.

**Fig. 5. Activation of ABINs is sufficient to induce ketamine-like behavioral effects.**
a Experimental timeline. Ascl1-Cre;hM3Dq mice received once-daily tamoxifen injections for 5 days. On day 7, a 3-week paradigm of unpredictable mild chronic stress (UCMS) was started. On day 28, saline, ketamine, or CNO was administered by intraperitoneal injection (i.p.) and 24 h later, mice underwent behavioral testing and euthanasia immediately afterward for sample collection. b Distance traveled in centimeters (saline n = 9, ketamine n = 9, CNO n = 6). ANOVA: ns. c Sociability Ratio. ANOVA: Treatment F_{2, 23} = 12.53 ***p = 0.0002; Tukey’s post hoc test: saline (n = 9) vs ketamine (n = 9) **p = 0.0075, saline vs CNO (n = 8) ***p = 0.0002, ketamine vs CNO ns p = 0.2535. d Novelty Ratio. ANOVA: Treatment F_{2, 23} = 9.602 ***p = 0.0009; Tukey’s post hoc test: saline (n = 9) vs ketamine (n = 9) **p = 0.0045, saline vs CNO (n = 8) **p = 0.0018, ketamine vs CNO ns p = 0.8751. e Time immobile in seconds. ANOVA: Treatment F_{2, 23} = 19.19 ****p < 0.0001; Tukey’s post hoc test: saline (n = 9) vs ketamine (n = 9) ***p = 0.0001, saline vs CNO (n = 8) ****p < 0.0001, ketamine vs CNO ns p = 0.6859. f Representative IHC of EGR1⁺ (red) and HA⁺ (green) staining. White arrows depict colocalization. Orthogonal views represent the coordinates of the cell marked with a black arrow. g Quantification of HA⁺ cells/mm³ in the DG (n = 5 mice/group). ANOVA: ns. h Quantification of HA⁺EGR1⁺ cells/mm³ (n = 5 mice/group). ANOVA: Treatment F_{2, 12} = 35.96 ****p < 0.0001; Tukey’s post hoc test: saline vs ketamine ***p = 0.0002, saline vs CNO, ****p < 0.0001, ketamine vs CNO ns p = 0.1202. i EGR1⁺ cells/mm³ (n = 5 mice/group). ANOVA: Treatment F_{2, 12} = 23.20 ****p < 0.0001; Tukey’s post hoc test: saline vs ketamine ***p = 0.0002, saline vs CNO ***p = 0.0002, ketamine vs CNO ns p = 0.9971. Data were presented as means ± s.e.m and were analyzed by t-test or ANOVA and Tukey’s post hoc test. Each replicate is a different mouse. For IHC, each point represents one mouse, with 3–5 sections averaged per mouse. Source data and complete statistics are provided as a source data file. Scale bar 25 μm.

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[1] Global Burden of Disease Study, C. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:743–800. doi: 10.1016/S0140-6736(15)60692-4. - DOI - PMC - PubMed

[2] Global Burden of Disease Study, C. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:743–800. doi: 10.1016/S0140-6736(15)60692-4. - DOI - PMC - PubMed

[3] Lepine JP, Briley M. The increasing burden of depression. Neuropsychiatr. Dis. Treat. 2011;7:3–7. - PMC - PubMed

[4] Lepine JP, Briley M. The increasing burden of depression. Neuropsychiatr. Dis. Treat. 2011;7:3–7. - PMC - PubMed

[5] Frazer A, Benmansour S. Delayed pharmacological effects of antidepressants. Mol. Psychiatry. 2002;7:S23–S28. doi: 10.1038/sj.mp.4001015. - DOI - PubMed

[6] Frazer A, Benmansour S. Delayed pharmacological effects of antidepressants. Mol. Psychiatry. 2002;7:S23–S28. doi: 10.1038/sj.mp.4001015. - DOI - PubMed

[7] Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am. J. Psychiatry. 2006;163:1905–1917. doi: 10.1176/ajp.2006.163.11.1905. - DOI - PubMed

[8] Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am. J. Psychiatry. 2006;163:1905–1917. doi: 10.1176/ajp.2006.163.11.1905. - DOI - PubMed

[9] Nelson JC, Charney DS. The symptoms of major depressive illness. Am. J. Psychiatry. 1981;138:1–13. - PubMed

[10] Nelson JC, Charney DS. The symptoms of major depressive illness. Am. J. Psychiatry. 1981;138:1–13. - PubMed

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Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice

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Ketamine activates adult-born immature granule neurons to rapidly alleviate depression-like behaviors in mice

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