Skip to main content
SpringerLink
Log in

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

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47(4):351–354

    Article  CAS  PubMed  Google Scholar 

  2. DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, Machado-Vieira R, Zarate CA Jr (2010) Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry 71(12):1605–1611. https://doi.org/10.4088/JCP.09m05327blu

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Price RB, Iosifescu DV, Murrough JW, Chang LC, Al Jurdi RK, Iqbal SZ, Soleimani L, Charney DS et al (2014) Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression. Depress Anxiety 31(4):335–343. https://doi.org/10.1002/da.22253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63(8):856–864. https://doi.org/10.1001/archpsyc.63.8.856

    Article  CAS  PubMed  Google Scholar 

  5. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, Rush AJ, Walters EE et al (2003) The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 289(23):3095–3105. https://doi.org/10.1001/jama.289.23.3095

    Article  PubMed  Google Scholar 

  6. Lim GY, Tam WW, Lu Y, Ho CS, Zhang MW, Ho RC (2018) Prevalence of depression in the community from 30 countries between 1994 and 2014. Sci Rep 8(1):2861. https://doi.org/10.1038/s41598-018-21243-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH et al (2006) Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 163(1):28–40. https://doi.org/10.1176/appi.ajp.163.1.28

    Article  PubMed  Google Scholar 

  8. Browne CA, Lucki I (2013) Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 4:161. https://doi.org/10.3389/fphar.2013.00161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Saland SK, Duclot F, Kabbaj M (2017) Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes. Curr Opin Behav Sci 14:19–26. https://doi.org/10.1016/j.cobeha.2016.11.002

    Article  PubMed  Google Scholar 

  10. Zanos P, Gould TD (2018) Mechanisms of ketamine action as an antidepressant. Mol Psychiatry 23(4):801–811. https://doi.org/10.1038/mp.2017.255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kadriu B, Musazzi L, Henter ID, Graves M, Popoli M, Zarate CA Jr (2018) Glutamatergic neurotransmission: pathway to developing novel rapid-acting antidepressant treatments. Int J Neuropsychopharmacol 22:119–135. https://doi.org/10.1093/ijnp/pyy094

    Article  CAS  PubMed Central  Google Scholar 

  12. Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P et al (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533(7604):481–486. https://doi.org/10.1038/nature17998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK (2008) Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 63(4):349–352. https://doi.org/10.1016/j.biopsych.2007.05.028

    Article  CAS  PubMed  Google Scholar 

  14. Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ (2014) Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry 29(7):419–423. https://doi.org/10.1016/j.eurpsy.2013.10.005

    Article  CAS  PubMed  Google Scholar 

  15. Koike H, Iijima M, Chaki S (2011) Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 224(1):107–111. https://doi.org/10.1016/j.bbr.2011.05.035

    Article  CAS  PubMed  Google Scholar 

  16. Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B, Kelley KW, Dantzer R (2013) NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice. Neuropsychopharmacology 38(9):1609–1616. https://doi.org/10.1038/npp.2013.71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475(7354):91–95. https://doi.org/10.1038/nature10130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM, Andreazza AC, Stertz L, Fries GR et al (2008) Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuro-Psychopharmacol Biol Psychiatry 32(1):140–144. https://doi.org/10.1016/j.pnpbp.2007.07.027

    Article  CAS  Google Scholar 

  19. Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK (2012) Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 71(11):996–1005. https://doi.org/10.1016/j.biopsych.2011.09.030

    Article  CAS  PubMed  Google Scholar 

  20. Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS (2014) BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol 18(1):pyu033. https://doi.org/10.1093/ijnp/pyu033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G et al (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959–964. https://doi.org/10.1126/science.1190287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Paul RK, Singh NS, Khadeer M, Moaddel R, Sanghvi M, Green CE, O'Loughlin K, Torjman MC et al (2014) (R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function. Anesthesiology 121(1):149–159. https://doi.org/10.1097/ALN.0000000000000285

    Article  CAS  PubMed  Google Scholar 

  23. Zito K, Scheuss V, Knott G, Hill T, Svoboda K (2009) Rapid functional maturation of nascent dendritic spines. Neuron 61(2):247–258. https://doi.org/10.1016/j.neuron.2008.10.054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fischer M, Kaech S, Knutti D, Matus A (1998) Rapid actin-based plasticity in dendritic spines. Neuron 20(5):847–854

    Article  CAS  PubMed  Google Scholar 

  25. Waller JA, Chen F, Sanchez C (2016) Vortioxetine promotes maturation of dendritic spines in vitro: a comparative study in hippocampal cultures. Neuropharmacology 103:143–154. https://doi.org/10.1016/j.neuropharm.2015.12.012

    Article  CAS  PubMed  Google Scholar 

  26. Widman AJ, McMahon LL (2018) Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. Proc Natl Acad Sci U S A 115(13):E3007–E3016. https://doi.org/10.1073/pnas.1718883115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nosyreva E, Szabla K, Autry AE, Ryazanov AG, Monteggia LM, Kavalali ET (2013) Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J Neurosci 33(16):6990–7002. https://doi.org/10.1523/JNEUROSCI.4998-12.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Janowsky DS, Overstreet DH, Nurnberger JI Jr (1994) Is cholinergic sensitivity a genetic marker for the affective disorders? Am J Med Genet 54(4):335–344. https://doi.org/10.1002/ajmg.1320540412

    Article  CAS  PubMed  Google Scholar 

  29. Overstreet DH (1986) Selective breeding for increased cholinergic function: development of a new animal model of depression. Biol Psychiatry 21(1):49–58

    Article  CAS  PubMed  Google Scholar 

  30. Overstreet DH, Russell RW (1982) Selective breeding for diisopropyl fluorophosphate-sensitivity: behavioural effects of cholinergic agonists and antagonists. Psychopharmacology 78(2):150–155

    Article  CAS  PubMed  Google Scholar 

  31. Overstreet DH, Russell RW, Helps SC, Messenger M (1979) Selective breeding for sensitivity to the anticholinesterase DFP. Psychopharmacology 65(1):15–20

    Article  CAS  PubMed  Google Scholar 

  32. Wegener G, Mathe AA, Neumann ID (2012) Selectively bred rodents as models of depression and anxiety. Curr Top Behav Neurosci 12:139–187. https://doi.org/10.1007/7854_2011_192

    Article  PubMed  Google Scholar 

  33. Overstreet DH, Wegener G (2013) The flinders sensitive line rat model of depression--25 years and still producing. Pharmacol Rev 65(1):143–155. https://doi.org/10.1124/pr.111.005397

    Article  CAS  PubMed  Google Scholar 

  34. Ardalan M, Wegener G, Polsinelli B, Madsen TM, Nyengaard JR (2016) Neurovascular plasticity of the hippocampus one week after a single dose of ketamine in genetic rat model of depression. Hippocampus 26(11):1414–1423. https://doi.org/10.1002/hipo.22617

    Article  CAS  PubMed  Google Scholar 

  35. Ardalan M, Wegener G, Rafati AH, Nyengaard JR (2017) S-Ketamine rapidly reverses synaptic and vascular deficits of hippocampus in genetic animal model of depression. Int J Neuropsychopharmacol 20(3):247–256. https://doi.org/10.1093/ijnp/pyw098

    Article  CAS  PubMed  Google Scholar 

  36. Chen F, Ardalan M, Elfving B, Wegener G, Madsen TM, Nyengaard JR (2018) Mitochondria are critical for BDNF-mediated synaptic and vascular plasticity of hippocampus following repeated electroconvulsive seizures. Int J Neuropsychopharmacol 21(3):291–304. https://doi.org/10.1093/ijnp/pyx115

    Article  CAS  PubMed  Google Scholar 

  37. Chen F, Madsen TM, Wegener G, Nyengaard JR (2010) Imipramine treatment increases the number of hippocampal synapses and neurons in a genetic animal model of depression. Hippocampus 20(12):1376–1384. https://doi.org/10.1002/hipo.20718

    Article  CAS  PubMed  Google Scholar 

  38. Ardalan M, Rafati AH, Nyengaard JR, Wegener G (2017) Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus. Br J Pharmacol 174(6):483–492. https://doi.org/10.1111/bph.13714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liebenberg N, Joca S, Wegener G (2015) Nitric oxide involvement in the antidepressant-like effect of ketamine in the Flinders sensitive line rat model of depression. Acta Neuropsychiatr 27(2):90–96. https://doi.org/10.1017/neu.2014.39

    Article  PubMed  Google Scholar 

  40. du Jardin KG, Liebenberg N, Cajina M, Müller HK, Elfving B, Sanchez C, Wegener G (2017) S-Ketamine mediates its acute and sustained antidepressant-like activity through a 5-HT1B receptor dependent mechanism in a genetic rat model of depression. Front Pharmacol 8:978. https://doi.org/10.3389/fphar.2017.00978

    Article  CAS  PubMed  Google Scholar 

  41. du Jardin KG, Liebenberg N, Müller HK, Elfving B, Sanchez C, Wegener G (2016) Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression. Psychopharmacology 233(14):2813–2825. https://doi.org/10.1007/s00213-016-4327-5

    Article  CAS  PubMed  Google Scholar 

  42. Al-Absi AR, Christensen HS, Sanchez C, Nyengaard JR (2018) Evaluation of semi-automatic 3D reconstruction for studying geometry of dendritic spines. J Chem Neuroanat 94:119–124. https://doi.org/10.1016/j.jchemneu.2018.10.008

    Article  CAS  PubMed  Google Scholar 

  43. Sholl DA (1953) Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 87(4):387–406

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Chen F, du Jardin KG, Waller JA, Sanchez C, Nyengaard JR, Wegener G (2016) Vortioxetine promotes early changes in dendritic morphology compared to fluoxetine in rat hippocampus. Eur Neuropsychopharmacol 26(2):234–245. https://doi.org/10.1016/j.euroneuro.2015.12.018

    Article  CAS  PubMed  Google Scholar 

  45. Nava N, Treccani G, Alabsi A, Müller HK, Elfving B, Popoli M, Wegener G, Nyengaard JR (2017) Temporal dynamics of acute stress-induced dendritic remodeling in medial prefrontal cortex and the protective effect of desipramine. Cereb Cortex 27(1):694–705. https://doi.org/10.1093/cercor/bhv254

    Article  PubMed  Google Scholar 

  46. Müller HK, Wegener G, Liebenberg N, Zarate CA Jr, Popoli M, Elfving B (2013) Ketamine regulates the presynaptic release machinery in the hippocampus. J Psychiatr Res 47(7):892–899. https://doi.org/10.1016/j.jpsychires.2013.03.008

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, Lepack A, Majik MS et al (2012) Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med 18(9):1413–1417. https://doi.org/10.1038/nm.2886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. MacQueen G, Frodl T (2011) The hippocampus in major depression: evidence for the convergence of the bench and bedside in psychiatric research? Mol Psychiatry 16(3):252–264. https://doi.org/10.1038/mp.2010.80

    Article  CAS  PubMed  Google Scholar 

  49. Price JL, Drevets WC (2010) Neurocircuitry of mood disorders. Neuropsychopharmacology 35(1):192–216. https://doi.org/10.1038/npp.2009.104

    Article  PubMed  Google Scholar 

  50. Qiao H, Li MX, Xu C, Chen HB, An SC, Ma XM (2016) Dendritic spines in depression: what we learned from animal models. Neural Plast 2016:8056370. https://doi.org/10.1155/2016/8056370

    Article  PubMed  PubMed Central  Google Scholar 

  51. Musazzi L, Treccani G, Popoli M (2015) Functional and structural remodeling of glutamate synapses in prefrontal and frontal cortex induced by behavioral stress. Front Psychiatry 6:60. https://doi.org/10.3389/fpsyt.2015.00060

    Article  PubMed  PubMed Central  Google Scholar 

  52. Walker AJ, Foley BM, Sutor SL, McGillivray JA, Frye MA, Tye SJ (2015) Peripheral proinflammatory markers associated with ketamine response in a preclinical model of antidepressant-resistance. Behav Brain Res 293:198–202. https://doi.org/10.1016/j.bbr.2015.07.026

    Article  CAS  PubMed  Google Scholar 

  53. Zhou W, Dong L, Wang N, Shi JY, Yang JJ, Zuo ZY, Zhou ZQ (2014) Akt mediates GSK-3beta phosphorylation in the rat prefrontal cortex during the process of ketamine exerting rapid antidepressant actions. Neuroimmunomodulation 21(4):183–188. https://doi.org/10.1159/000356517

    Article  CAS  PubMed  Google Scholar 

  54. Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, Hu H (2018) Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554(7692):317–322. https://doi.org/10.1038/nature25509

    Article  CAS  PubMed  Google Scholar 

  55. Burgdorf J, Zhang XL, Nicholson KL, Balster RL, Leander JD, Stanton PK, Gross AL, Kroes RA et al (2013) GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology 38(5):729–742. https://doi.org/10.1038/npp.2012.246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu RJ, Fuchikami M, Dwyer JM, Lepack AE, Duman RS, Aghajanian GK (2013) GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology 38(11):2268–2277. https://doi.org/10.1038/npp.2013.128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ruddy RM, Chen Y, Milenkovic M, Ramsey AJ (2015) Differential effects of NMDA receptor antagonism on spine density. Synapse 69(1):52–56. https://doi.org/10.1002/syn.21784

    Article  CAS  PubMed  Google Scholar 

  58. Phoumthipphavong V, Barthas F, Hassett S, Kwan AC (2016) Longitudinal effects of ketamine on dendritic architecture in vivo in the mouse medial frontal cortex. eNeuro 3(2). https://doi.org/10.1523/ENEURO.0133-15.2016

    Article  PubMed  PubMed Central  Google Scholar 

  59. Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H, Li XY, Aghajanian G et al (2011) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69(8):754–761. https://doi.org/10.1016/j.biopsych.2010.12.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang WJ, Wang HH, Lv YD, Liu CC, Sun WY, Tian LJ (2018) Downregulation of Egr-1 expression level via GluN2B underlies the antidepressant effects of ketamine in a chronic unpredictable stress animal model of depression. Neuroscience 372:38–45. https://doi.org/10.1016/j.neuroscience.2017.12.045

    Article  CAS  PubMed  Google Scholar 

  61. Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, Dong C, Hashimoto K (2015) R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry 5:e632. https://doi.org/10.1038/tp.2015.136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Dong C, Zhang JC, Yao W, Ren Q, Ma M, Yang C, Chaki S, Hashimoto K (2017) Rapid and sustained antidepressant action of the mGlu2/3 receptor antagonist MGS0039 in the social defeat stress model: comparison with ketamine. Int J Neuropsychopharmacol 20(3):228–236. https://doi.org/10.1093/ijnp/pyw089

    Article  CAS  PubMed  Google Scholar 

  63. Sarkar A, Kabbaj M (2016) Sex differences in effects of ketamine on behavior, spine density, and synaptic proteins in socially isolated rats. Biol Psychiatry 80(6):448–456. https://doi.org/10.1016/j.biopsych.2015.12.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Widman AJ, Stewart AE, Erb EM, Gardner E, McMahon LL (2018) Intravascular ketamine increases theta-burst but not high frequency tetanus induced LTP at CA3-CA1 synapses within three hours and devoid of an increase in spine density. Front Synaptic Neurosci 10:8. https://doi.org/10.3389/fnsyn.2018.00008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Pryazhnikov E, Mugantseva E, Casarotto P, Kolikova J, Fred SM, Toptunov D, Afzalov R, Hotulainen P et al (2018) Longitudinal two-photon imaging in somatosensory cortex of behaving mice reveals dendritic spine formation enhancement by subchronic administration of low-dose ketamine. Sci Rep 8(1):6464. https://doi.org/10.1038/s41598-018-24933-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sales AJ, Fogaca MV, Sartim AG, Pereira VS, Wegener G, Guimaraes FS, Joca SRL (2018) Cannabidiol induces rapid and sustained antidepressant-like effects through increased BDNF signaling and synaptogenesis in the prefrontal cortex. Mol Neurobiol 56:1070–1081. https://doi.org/10.1007/s12035-018-1143-4

    Article  CAS  PubMed  Google Scholar 

  67. Dunaevsky A, Tashiro A, Majewska A, Mason C, Yuste R (1999) Developmental regulation of spine motility in the mammalian central nervous system. Proc Natl Acad Sci U S A 96(23):13438–13443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kwon HB, Sabatini BL (2011) Glutamate induces de novo growth of functional spines in developing cortex. Nature 474(7349):100–104. https://doi.org/10.1038/nature09986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. MacLusky NJ, Luine VN, Hajszan T, Leranth C (2005) The 17alpha and 17beta isomers of estradiol both induce rapid spine synapse formation in the CA1 hippocampal subfield of ovariectomized female rats. Endocrinology 146(1):287–293. https://doi.org/10.1210/en.2004-0730

    Article  CAS  PubMed  Google Scholar 

  70. Dos Santos M, Salery M, Forget B, Garcia Perez MA, Betuing S, Boudier T, Vanhoutte P, Caboche J et al (2017) 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 82(11):806–818. https://doi.org/10.1016/j.biopsych.2017.03.014

    Article  CAS  PubMed  Google Scholar 

  71. Spruston N (2008) Pyramidal neurons: dendritic structure and synaptic integration. Nat Rev Neurosci 9(3):206–221. https://doi.org/10.1038/nrn2286

    Article  CAS  PubMed  Google Scholar 

  72. Yang C, Hu YM, Zhou ZQ, Zhang GF, Yang JJ (2013) Acute administration of ketamine in rats increases hippocampal BDNF and mTOR levels during forced swimming test. Ups J Med Sci 118(1):3–8. https://doi.org/10.3109/03009734.2012.724118

    Article  PubMed  PubMed Central  Google Scholar 

  73. Song M, Martinowich K, Lee FS (2017) BDNF at the synapse: why location matters. Mol Psychiatry 22(10):1370–1375. https://doi.org/10.1038/mp.2017.144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Treccani G, Gaarn du Jardin K, Wegener G, Müller HK (2016) Differential expression of postsynaptic NMDA and AMPA receptor subunits in the hippocampus and prefrontal cortex of the flinders sensitive line rat model of depression. Synapse 70(11):471–474. https://doi.org/10.1002/syn.21918

    Article  CAS  PubMed  Google Scholar 

  75. Abildgaard A, Solskov L, Volke V, Harvey BH, Lund S, Wegener G (2011) A high-fat diet exacerbates depressive-like behavior in the Flinders Sensitive Line (FSL) rat, a genetic model of depression. Psychoneuroendocrinology 36(5):623–633. https://doi.org/10.1016/j.psyneuen.2010.09.004

    Article  CAS  PubMed  Google Scholar 

  76. Eriksson TM, Delagrange P, Spedding M, Popoli M, Mathe AA, Ogren SO, Svenningsson P (2012) Emotional memory impairments in a genetic rat model of depression: involvement of 5-HT/MEK/Arc signaling in restoration. Mol Psychiatry 17(2):173–184. https://doi.org/10.1038/mp.2010.131

    Article  CAS  PubMed  Google Scholar 

  77. Gomez-Galan M, De Bundel D, Van Eeckhaut A, Smolders I, Lindskog M (2013) Dysfunctional astrocytic regulation of glutamate transmission in a rat model of depression. Mol Psychiatry 18(5):582–594. https://doi.org/10.1038/mp.2012.10

    Article  CAS  PubMed  Google Scholar 

  78. Shiraishi Y, Mizutani A, Mikoshiba K, Furuichi T (2003) 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 22(2):188–201

    Article  CAS  PubMed  Google Scholar 

  79. Pontrello CG, Sun MY, Lin A, Fiacco TA, DeFea KA, Ethell IM (2012) Cofilin under control of beta-arrestin-2 in NMDA-dependent dendritic spine plasticity, long-term depression (LTD), and learning. Proc Natl Acad Sci U S A 109(7):E442–E451. https://doi.org/10.1073/pnas.1118803109

    Article  PubMed  PubMed Central  Google Scholar 

  80. Duman RS, Aghajanian GK (2012) Synaptic dysfunction in depression: potential therapeutic targets. Science 338(6103):68–72. https://doi.org/10.1126/science.1222939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

Centre for Stochastic Geometry and Advanced Bioimaging is supported by Villum Foundation. We gratefully acknowledge the support by the Core Facility Microscopy of the Institute of Molecular Biology (IMB) in Mainz, Germany and Ferruccio Bosetti for IT consulting. We thank Maiken Krogsbæk Mikkelsen for her assistance with microscopy.

Funding

Funding was provided for G.T. by a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation and a postdoctoral research grant from the Danish Council for Independent Research (DFF–5053-00103). L.M. was supported by CARIPLO Foundation (Biomedical Science for Young Scientists, Prog. 2014-1133). The work was supported by grants from Dagmar Marshall’s Foundation, Direktør Jacob Madsen and Hustru Olga Madsen’s Foundation, Aase og Ejnar Danielsen’s Foundation, Kong Christian den Tiendes Foundation, and Direktør Kurt Bønnelycke and Hustru Fru Grethe Bønnelycke’s Foundation.

Author information

Author notes

  1. Giulia Treccani and Maryam Ardalan contributed equally to this work.

Authors and Affiliations

  1. Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Skovagervej 72, 8240, Risskov, Denmark

    Giulia Treccani, Maryam Ardalan, Fenghua Chen, Gregers Wegener & Heidi Kaastrup Müller

  2. Department of Psychiatry and Psychotherapy, Johannes Gutenberg University Medical Center Mainz, Untere Zahlbacher Straße 8, Mainz, Germany

    Giulia Treccani

  3. Deutsches Resilienz Zentrum (DRZ) gGmbH, Mainz, Germany

    Giulia Treccani

  4. Laboratory of Neuropsychopharmacology and Functional Neurogenomics - Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases, University of Milano, Milan, Italy

    Laura Musazzi & Maurizio Popoli

  5. AUGUST Centre, Department of Clinical Medicine, Aarhus University, Risskov, Denmark

    Gregers Wegener

  6. Core Center for Molecular Morphology, Section for Stereology and Microscopy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

    Jens Randel Nyengaard

  7. Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University, Aarhus, Denmark

    Jens Randel Nyengaard

Authors
  1. Giulia Treccani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maryam Ardalan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fenghua Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura Musazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maurizio Popoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gregers Wegener
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jens Randel Nyengaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Heidi Kaastrup Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.T., M.A., and H.K.M performed the experiments, analyzed and interpreted the results. G.T. and H.K.M. wrote the paper. All co-authors provided conceptual advice, commented on the manuscript, and approved the final version before submission.

Corresponding author

Correspondence to Heidi Kaastrup Müller.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 135 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Treccani, G., Ardalan, M., Chen, F. et al. S-Ketamine Reverses Hippocampal Dendritic Spine Deficits in Flinders Sensitive Line Rats Within 1 h of Administration. Mol Neurobiol 56, 7368–7379 (2019). https://doi.org/10.1007/s12035-019-1613-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-019-1613-3

Keywords

Search

Navigation