S-Ketamine Reverses Hippocampal Dendritic Spine Deficits in Flinders Sensitive Line Rats Within 1 h of Administration

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2019 May 1

PMID 31037646

Citations 30

Authors

Giulia Treccani

Maryam Ardalan

Fenghua Chen

Laura Musazzi

Maurizio Popoli

Gregers Wegener

Jens Randel Nyengaard

Heidi Kaastrup Muller

Affiliations

Soon will be listed here.

Abstract

When administered as a single subanesthetic dose, the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, produces rapid (within hours) and relatively sustained antidepressant actions even in treatment-resistant patients. Preclinical studies have shown that ketamine increases dendritic spine density and synaptic proteins in brain areas critical for the actions of antidepressants, yet the temporal relationship between structural changes and the onset of antidepressant action remains poorly understood. In this study, we examined the effects of a single dose of S-ketamine (15 mg/kg) on dendritic length, dendritic arborization, spine density, and spine morphology in the Flinders Sensitive and Flinders Resistant Line (FSL/FRL) rat model of depression. We found that already 1 h after injection with ketamine, apical dendritic spine deficits in CA1 pyramidal neurons of FSL rats were completely restored. Notably, the observed increase in spine density was attributable to regulation of both mushroom and long-thin spines. In contrast, ketamine had no effect on dendritic spine density in FRL rats. On the molecular level, ketamine normalized elevated levels of phospho-cofilin and the NMDA receptor subunits GluN2A and GluN2B and reversed homer3 deficiency in hippocampal synaptosomes of FSL rats. Taken together, our data suggest that rapid formation of new spines may provide an important structural substrate during the initial phase of ketamine's antidepressant action.

Citing Articles

Neurophysiological correlates of ketamine-induced dissociative state in bipolar disorder: insights from real-world clinical settings.

Agnorelli C, Cinti A, Barilla G, Lomi F, Scoccia A, Benelli A Mol Psychiatry. 2025; .

PMID: 39809847 DOI: 10.1038/s41380-025-02889-2.

An Updated Bio-Behavioral Profile of the Flinders Sensitive Line Rat: Reviewing the Findings of the Past Decade.

Steyn S Pharmacol Res Perspect. 2025; 13(1):e70058.

PMID: 39786312 PMC: 11717001. DOI: 10.1002/prp2.70058.

Beyond NMDA Receptors: A Narrative Review of Ketamine's Rapid and Multifaceted Mechanisms in Depression Treatment.

Antos Z, Zukow X, Bursztynowicz L, Jakubow P Int J Mol Sci. 2025; 25(24.

PMID: 39769420 PMC: 11728282. DOI: 10.3390/ijms252413658.

Memantine Alleviates PTSD-like Symptoms and Improves Dendritic Arborization through Modulation of the HPA Axis and Neuroinflammation in Rats.

Bommaraju S, Dhokne M, Rakeshkumar P, Datusalia A Neurochem Res. 2024; 50(1):58.

PMID: 39673655 DOI: 10.1007/s11064-024-04315-5.

S-ketamine alleviates depression-like behavior and hippocampal neuroplasticity in the offspring of mice that experience prenatal stress.

Zhang Y, Wei C, Wang P, Zheng L, Cheng Y, Ren Z Sci Rep. 2024; 14(1):26929.

PMID: 39505897 PMC: 11542010. DOI: 10.1038/s41598-024-76226-y.

References

Shiraishi Y, Mizutani A, Mikoshiba K, Furuichi T . Coincidence in dendritic clustering and synaptic targeting of homer proteins and NMDA receptor complex proteins NR2B and PSD95 during development of cultured hippocampal neurons. Mol Cell Neurosci. 2003; 22(2):188-201. DOI: 10.1016/s1044-7431(03)00037-x. View

Dunaevsky A, Tashiro A, Majewska A, Mason C, Yuste R . Developmental regulation of spine motility in the mammalian central nervous system. Proc Natl Acad Sci U S A. 1999; 96(23):13438-43. PMC: 23966. DOI: 10.1073/pnas.96.23.13438. View

Dong C, Zhang J, Yao W, Ren Q, Ma M, Yang C . Rapid and Sustained Antidepressant Action of the mGlu2/3 Receptor Antagonist MGS0039 in the Social Defeat Stress Model: Comparison with Ketamine. Int J Neuropsychopharmacol. 2016; 20(3):228-236. PMC: 5408970. DOI: 10.1093/ijnp/pyw089. View

Qiao H, Li M, Xu C, Chen H, An S, Ma X . Dendritic Spines in Depression: What We Learned from Animal Models. Neural Plast. 2016; 2016:8056370. PMC: 4736982. DOI: 10.1155/2016/8056370. View

Widman A, McMahon L . Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. Proc Natl Acad Sci U S A. 2018; 115(13):E3007-E3016. PMC: 5879689. DOI: 10.1073/pnas.1718883115. View

Maeng S, Zarate Jr C, Du J, Schloesser R, McCammon J, Chen G . Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2007; 63(4):349-52. DOI: 10.1016/j.biopsych.2007.05.028. View

Zhou W, Wang N, Yang C, Li X, Zhou Z, Yang J . Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry. 2013; 29(7):419-23. DOI: 10.1016/j.eurpsy.2013.10.005. View

Dos Santos M, Salery M, Forget B, Garcia Perez M, Betuing S, Boudier T . Rapid Synaptogenesis in the Nucleus Accumbens Is Induced by a Single Cocaine Administration and Stabilized by Mitogen-Activated Protein Kinase Interacting Kinase-1 Activity. Biol Psychiatry. 2017; 82(11):806-818. DOI: 10.1016/j.biopsych.2017.03.014. View

Nosyreva E, Szabla K, Autry A, Ryazanov A, Monteggia L, Kavalali E . Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J Neurosci. 2013; 33(16):6990-7002. PMC: 3661220. DOI: 10.1523/JNEUROSCI.4998-12.2013. View

10.

Overstreet D, RUSSELL R . Selective breeding for diisopropyl fluorophosphate-sensitivity: behavioural effects of cholinergic agonists and antagonists. Psychopharmacology (Berl). 1982; 78(2):150-5. DOI: 10.1007/BF00432254. View

11.

Zarate Jr C, Singh J, Carlson P, Brutsche N, Ameli R, Luckenbaugh D . A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006; 63(8):856-64. DOI: 10.1001/archpsyc.63.8.856. View

12.

Ardalan M, Wegener G, Rafati A, Nyengaard J . S-Ketamine Rapidly Reverses Synaptic and Vascular Deficits of Hippocampus in Genetic Animal Model of Depression. Int J Neuropsychopharmacol. 2016; 20(3):247-256. PMC: 5408982. DOI: 10.1093/ijnp/pyw098. View

13.

Pontrello C, Sun M, Lin A, Fiacco T, DeFea K, Ethell I . Cofilin under control of β-arrestin-2 in NMDA-dependent dendritic spine plasticity, long-term depression (LTD), and learning. Proc Natl Acad Sci U S A. 2012; 109(7):E442-51. PMC: 3289389. DOI: 10.1073/pnas.1118803109. View

14.

Lim G, Tam W, Lu Y, Ho C, Zhang M, Ho R . Prevalence of Depression in the Community from 30 Countries between 1994 and 2014. Sci Rep. 2018; 8(1):2861. PMC: 5809481. DOI: 10.1038/s41598-018-21243-x. View

15.

Chen F, Gaarn Du Jardin K, Waller J, Sanchez C, Nyengaard J, Wegener G . Vortioxetine promotes early changes in dendritic morphology compared to fluoxetine in rat hippocampus. Eur Neuropsychopharmacol. 2015; 26(2):234-245. DOI: 10.1016/j.euroneuro.2015.12.018. View

16.

Saland S, Duclot F, Kabbaj M . Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes. Curr Opin Behav Sci. 2017; 14:19-26. PMC: 5456295. DOI: 10.1016/j.cobeha.2016.11.002. View

17.

Zhang W, Wang H, Lv Y, Liu C, Sun W, Tian L . Downregulation of Egr-1 Expression Level via GluN2B Underlies the Antidepressant Effects of Ketamine in a Chronic Unpredictable Stress Animal Model of Depression. Neuroscience. 2018; 372:38-45. DOI: 10.1016/j.neuroscience.2017.12.045. View

18.

Sales A, Fogaca M, Sartim A, Pereira V, Wegener G, Guimaraes F . Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex. Mol Neurobiol. 2018; 56(2):1070-1081. DOI: 10.1007/s12035-018-1143-4. View

19.

Eriksson T, Delagrange P, Spedding M, Popoli M, Mathe A, Ogren S . Emotional memory impairments in a genetic rat model of depression: involvement of 5-HT/MEK/Arc signaling in restoration. Mol Psychiatry. 2011; 17(2):173-84. PMC: 3265836. DOI: 10.1038/mp.2010.131. View

20.

Waller J, Chen F, Sanchez C . Vortioxetine promotes maturation of dendritic spines in vitro: A comparative study in hippocampal cultures. Neuropharmacology. 2015; 103:143-54. DOI: 10.1016/j.neuropharm.2015.12.012. View