Rapid effects of S-ketamine on the morphology of hippocampal astrocytes and BDNF serum levels in a sex-dependent manner
Introduction
Major depressive disorder (MDD) is a serious neuropsychological disorder with a higher prevalence in women (8–10%) than in men (3–5%) (Kessler et al., 2005). Currently three main therapeutic strategies (pharmacotherapy, psychotherapy and electroconvulsive therapy) are used for MDD but none of them provides an optimal rapid and sustained clinical remission. The delay in response to conventional antidepressants, despite the rapid actions at the pharmacological target, leaves severely depressed patients at a risk of suicide. Consequently, there is an unmet need to develop more efficient drugs with a fast onset of antidepressant effect, minimal side effects and broader efficacy. The fast onset of action of glutamate receptor modulators, especially ketamine, is a promising feature for developing antidepressant drugs. In clinical studies, the antidepressant efficacy of ketamine in treatment-resistant depression has been reported between 25% and 100% with the onset of action within hours (Drewniany et al., 2015; Henter et al., 2017; Jaso et al., 2017; Murrough et al., 2013a, 2013b; Pereira et al., 2019; Sanacora et al., 2017). Preclinical studies have suggested that the rapid antidepressant effect of ketamine on the behavior in rodents is modulated differently in the prefrontal cortex (through mammalian target of rapamycin pathway, mTOR) and hippocampus (regulating eukaryotic elongation factor 2 (eEF2) kinase) (Zanos and Gould, 2018). Furthermore, the studies indicate that the release of brain-derived neurotrophic factor (BDNF) is required for the rapid antidepressant effect of ketamine (Autry et al., 2011; Huang et al., 2017; Lepack et al., 2015). In a different context, it has been reported that dysfunction of astrocytes results in the impairment of the synthesis of neurotrophic and angiogenic factors and glutamate metabolism (Acker et al., 2001; Erickson et al., 2001), and post-mortem studies have shown a reduction in the number of glia cells in the frontal cortex of depressed patients (Cotter et al., 2002; Rajkowska and Stockmeier, 2013). Crucially, it is not clear whether the structural alteration of astrocytes, including changes in their number and morphology, is the cause or the consequence of functional impairment of astrocytes in psychiatric disorders. Interestingly, female Sprague-Dawley rats respond to a lower dose of ketamine (2.5 mg/kg) (Carrier and Kabbaj, 2013), and the fast and sustained antidepressant-like effects of ketamine in the forced swim test (FST) are sex-dependent, suggesting that presynaptic release of glutamate in the hippocampus by ketamine could be sex-dependent (Franceschelli et al., 2015).
Therefore, the overriding aims of the present work were to examine possible effects of sex on the structural alterations of astrocytes in depression following ketamine, paired with investigations of the BDNF levels. Specifically, we examined (i) the morphological alteration of hippocampal astrocytes; and (ii) the serum levels of BDNF, one hour after S-ketamine treatment of male and female FSL rats, a genetic rat model of depression.
Section snippets
Animals
Adult male and female Flinders Sensitive Line (FSL) rats (male, n = 12; female, n = 10) with the average age of 90 days originating from the colonies at the Karolinska Institute were included in this study. Female rats housed in same cages/same conditions synchronize their estrous cycle (Jimenez-Vasquez et al., 2000; Saland and Kabbaj, 2018).
Animal care was carried out in accordance with the guidelines issued by the Danish committee on animal ethics (permission id 2012-15-2934-00254). The rats
Volumes of the hippocampal subregions
In the first set of observations, we examined the volumes of the hippocampal subregions. The volumes of the hippocampal subregions were notably influenced by sex (F1,18=27.79 to 62.28; p = 0.000). Moreover, ketamine treatment had significant effects on the volumes of CA1.SR and MDG (F1,18=15.87, p = 0.001; F1,18=7.31, p = 0.01). We found a significant baseline difference in the volumes of the CA1.SR and MDG subfields of the hippocampus between depressed male-vehicle and female-vehicle rats (p
Discussion
The main findings in the present study are the difference between sexes in response to S-ketamine and the rapid effect observed on the morphological levels, one hour following S-ketamine administration.
To test the hypothesis of sex-differentiated cellular and neurotrophic factor responses to S-ketamine, we compared the morphological alteration of the hippocampal astrocytes and the serum levels of BDNF one hour after a single dose of S-ketamine in male and female FSL rats. This question is
Conclusion
Our results indicate that S-ketamine induces alteration of the structural plasticity of hippocampus as well as morphological alteration of hippocampal astrocytes and affects the serum level of BDNF within one hour after a single administration in a sex-dependent manner. The translational validity of these findings in humans is currently unknown.
Role of the funding source
This work was supported by the Lundbeck Foundation and the Aarhus University Research Foundation (AU-Ideas initiative (eMOOD)) and EU Horizon 2020 (ExEDE). Maryam Ardalan (MA) was supported by the Lundbeck Foundation and Aleksander A.Mathe (AAM) by the Swedish Medical Research Council grant 10414, 2015-02966, 2016-02955. GW declares having received lecture fees from H. Lundbeck A/S, Servier SA, Astra Zeneca AB, Eli Lilly A/S, Sun Pharma Pty, and Pfizer Inc.
Funding sources had no further role in
Contributors
MA, GW, AAM and CZ designed the study. MA, BF, AHR and MM performed the experiments, data collection, and data analysis. MA and GW interpreted the results and wrote the manuscript. All authors provided the conceptual advice, commented on the manuscript, and approved the final version of the manuscript for submission. Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of
Declaration of Competing Interest
All authors declare that they have no conflicts of interest.
Acknowledgments
The paper is part of a PhD project by Maryam Ardalan, supervised by Gregers Wegener (animal models, design and pharmacological intervention) and Jens Randel Nyengaard (stereological design). We are grateful to Heidi Kaastrup Müller for her scientific consulting in this project.
References (49)
- et al.
Cell type specific expression of vascular endothelial growth factor and angiopoietin-1 and -2 suggests an important role of astrocytes in cerebellar vascularization
Mech. Dev.
(2001) - et al.
Glial cells as targets and producers of neurotrophins
Int. Rev. Cytol.
(2000) - et al.
Sex differences in the antidepressant-like effects of ketamine
Neuropharmacology
(2013) - et al.
Female flinders sensitive line rats show estrous cycle-independent depression-like behavior and altered tryptophan metabolism
Neuroscience
(2016) - et al.
Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naive and "depressed" mice exposed to chronic mild stress
Neuroscience
(2015) - et al.
Ketamine dose-dependently induces high-frequency oscillations in the nucleus accumbens in freely moving rats
Biol. Psychiatry
(2006) - et al.
Early maternal separation alters neuropeptide Y concentrations in selected brain regions in adult rats
Brain Res. Dev. Brain Res.
(2001) - et al.
Neuropeptide Y in male and female brains of flinders sensitive line, a rat model of depression. Effects of electroconvulsive stimuli
J. Psychiatr. Res.
(2000) - et al.
Brain-derived neurotrophic factor val66met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex
Biol. Psychiatry
(2012) - et al.
Ketamine regulates the presynaptic release machinery in the hippocampus
J. Psychiatr. Res.
(2013)
Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression
Biol. Psychiatry
Regulation of glutamate transporter glast and GLT-1 expression in astrocytes by estrogen
Brain Res. Mol. Brain Res.
Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression
Biol. Psychiatry
Cellular changes in the postmortem hippocampus in major depression
Biol. Psychiatry
Sex differences in the temporal neuromolecular and synaptogenic effects of the rapid-acting antidepressant drug ketamine in the mouse brain
Neuroscience
Repeated ketamine treatment induces sex-specific behavioral and neurochemical effects in mice
Behav. Brain Res.
The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies)
Prog. Brain Res.
Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus
Br. J. Pharmacol.
S-Ketamine rapidly reverses synaptic and vascular deficits of hippocampus in genetic animal model of depression
Int. J. Neuropsychopharmacol
NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses
Nature
Gonadal hormone modulation of dendrites in the mammalian CNS
J. Neurobiol.
Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder
Cereb. Cortex
Rapid-onset antidepressant action of ketamine: potential revolution in understanding and future pharmacologic treatment of depression
J. Clin. Pharm. Ther.
Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression
Psychopharmacology
Cited by (23)
Ketamine, benzoate, and sarcosine for treating depression
2023, NeuropharmacologyCitation Excerpt :Similar effects of esketamine and arketamine were noted. Esketamine injection increased the BDNF level in serum (Ardalan et al., 2020) and the number of nonperforated and perforated synapses (Ardalan et al., 2017) in Flinders Sensitive Line rats. Although the NMDAR antagonist effect of arketamine is weaker than that of ketamine or esketamine (Hashimoto, 2020a; Wei et al., 2022a), arketamine exhibits more potency on dendritic spine density, BDNF-TrkB signaling, and synaptogenesis compared with esketamine (Yang et al., 2015a; Yao et al., 2022; Zhang et al., 2019).
Real-world experience of esketamine use to manage treatment-resistant depression: A multicentric study on safety and effectiveness (REAL-ESK study)
2022, Journal of Affective DisordersCitation Excerpt :Reduced glutamate levels have been reported in prefrontal areas of TRD subjects (Kim and Na, 2016). Furthermore, the glutamatergic hypothesis has also been supported by the antidepressant efficacy of ketamine and esketamine, two drugs that modulate glutamatergic activity by antagonising the ionotropic N-methyl-d-aspartate (NMDA) receptor (DiazGranados et al., 2010; Zarate et al., 2006, 2012) and able to determine neuroplasticity changes via the mTOR/BDNF signaling pathways (Ardalan et al., 2020; Ricci et al., 2011). Although limited in its clinical use due to its intravenous administration, ketamine has been demonstrated to be effective in TRD patients, with response rates ranging from 30 % to 70 % (Shin and Kim, 2020).
Stress, mental disorder and ketamine as a novel, rapid acting treatment
2022, European NeuropsychopharmacologyRapid and sustained restoration of astrocytic functions by ketamine in depression model mice
2022, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Reduced GLT-1 level has been shown to be sufficient to induce depression-like phenotypes in mice [9,10], while pharmacological enhancement of GLT-1 functions reverses depression phenotypes [11]. Ketamine has been shown to affect the functions and structures of astrocytes, including larger astrocyte volume [12] and normalization of reduced GFAP level [13]. Thus, a better understanding of the role of astrocytes play in the anti-depression process of ketamine is important.
Effects of stress on endophenotypes of suicide across species: A role for ketamine in risk mitigation
2022, Neurobiology of StressCitation Excerpt :In rats, high doses of ketamine (20–30 mg/kg), which fail to ameliorate stress-induced depressive symptoms (Donahue et al., 2014), inhibit astrocytic activation (Shibakawa et al., 2005)—a mechanism that likely underlies its analgesic properties (Mei et al., 2010). By contrast, lower doses that ameliorate CMS-induced depressive phenotypes (2–15 mg/kg) rapidly activate astrocytes and subsequently stimulate BDNF synthesis (Ardalan et al., 2020). In fact, blocking astrocyte activation precludes the antidepressant benefits of ketamine (but not scopolamine) (Wang et al., 2018), implicating an important role for astrocytic activation in ketamine's antidepressant effects.