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PMID: 27066532 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Longitudinal Effects of Ketamine on Dendritic Architecture In Vivo in the Mouse Medial Frontal Cortex.

eNeuro ·Vol. 3 ·No. 2 ·2016-00-00

Phoumthipphavong V, Barthas F, Hassett S, Kwan AC

Abstract

A single subanesthetic dose of ketamine, an NMDA receptor antagonist, leads to fast-acting antidepressant effects. In rodent models, systemic ketamine is associated with higher dendritic spine density in the prefrontal cortex, reflecting structural remodeling that may underlie the behavioral changes. However, turnover of dendritic spines is a dynamic process in vivo, and the longitudinal effects of ketamine on structural plasticity remain unclear. The purpose of the current study is to use subcellular resolution optical imaging to determine the time course of dendritic alterations in vivo following systemic ketamine administration in mice. We used two-photon microscopy to visualize repeatedly the same set of dendritic branches in the mouse medial frontal cortex (MFC) before and after a single injection of ketamine or saline. Compared to controls, ketamine-injected mice had higher dendritic spine density in MFC for up to 2 weeks. This prolonged increase in spine density was driven by an elevated spine formation rate, and not by changes in the spine elimination rate. A fraction of the new spines following ketamine injection was persistent, which is indicative of functional synapses. In a few cases, we also observed retraction of distal apical tuft branches on the day immediately after ketamine administration. These results indicate that following systemic ketamine administration, certain dendritic inputs in MFC are removed immediately, while others are added gradually. These dynamic structural modifications are consistent with a model of ketamine action in which the net effect is a rebalancing of synaptic inputs received by frontal cortical neurons.

Keywords
dendrites dendritic spines frontal cortex ketamine structural plasticity two-photon microscopy
MeSH Terms
Analysis of Variance Animals Bacterial Proteins/genetics,metabolism Dendrites/drug effects Dendritic Spines/drug effects Excitatory Amino Acid Antagonists/pharmacology Female Frontal Lobe/cytology,diagnostic imaging Green Fluorescent Proteins/genetics,metabolism Ketamine/pharmacology Luminescent Proteins/genetics,metabolism Male Mice Mice, Transgenic Microscopy, Fluorescence Neurons/cytology,drug effects Thy-1 Antigens/genetics,metabolism Time Factors
Chemicals
Bacterial Proteins Excitatory Amino Acid Antagonists Luminescent Proteins Thy-1 Antigens yellow fluorescent protein, Bacteria Green Fluorescent Proteins Ketamine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Phoumthipphavong Victoria
Department of Psychiatry, Yale University , New Haven, Connecticut 06511.
Barthas Florent
Department of Psychiatry, Yale University , New Haven, Connecticut 06511.
Hassett Samantha
Department of Psychiatry, Yale University , New Haven, Connecticut 06511.
Kwan Alex C ORCID
Department of Psychiatry, Yale University, New Haven, Connecticut 06511; Department of Neuroscience, Yale University, New Haven, Connecticut 06511.
References (58)
58 references, click to expand
  1. Effects of ketamine, MK-801, and amphetamine on regional brain 2-deoxyglucose uptake in freely moving mice.
    Neuropsychopharmacology. 2000 Apr;22(4):400-12 PMID: 10700659
  2. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses.
    Nature. 2011 Jul 7;475(7354):91-5 PMID: 21677641
  3. Effects of striatal ΔFosB overexpression and ketamine on social defeat stress-induced anhedonia in mice.
    Biol Psychiatry. 2014 Oct 1;76(7):550-8 PMID: 24495460
  4. A pyramid approach to subpixel registration based on intensity.
    IEEE Trans Image Process. 1998;7(1):27-41 PMID: 18267377
  5. Stress-induced dendritic remodeling in the prefrontal cortex is circuit specific.
    Cereb Cortex. 2009 Oct;19(10):2479-84 PMID: 19193712
  6. Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window.
    Nat Protoc. 2009;4(8):1128-44 PMID: 19617885
  7. Structural and synaptic plasticity in stress-related disorders.
    Rev Neurosci. 2011;22(5):535-49 PMID: 21967517
  8. ScanImage: flexible software for operating laser scanning microscopes.
    Biomed Eng Online. 2003 May 17;2:13 PMID: 12801419
  9. Chronic stress causes frontostriatal reorganization and affects decision-making.
    Science. 2009 Jul 31;325(5940):621-5 PMID: 19644122
  10. Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat.
    Brain Struct Funct. 2007 Sep;212(2):149-79 PMID: 17717690
  11. Stress-induced grey matter loss determined by MRI is primarily due to loss of dendrites and their synapses.
    Mol Neurobiol. 2013 Apr;47(2):645-61 PMID: 23138690
  12. Cocaine-induced structural plasticity in frontal cortex correlates with conditioned place preference.
    Nat Neurosci. 2013 Oct;16(10):1367-9 PMID: 23974707
  13. Ketamine Strengthens CRF-Activated Amygdala Inputs to Basal Dendrites in mPFC Layer V Pyramidal Cells in the Prelimbic but not Infralimbic Subregion, A Key Suppressor of Stress Responses.
    Neuropsychopharmacology. 2015 Aug;40(9):2066-75 PMID: 25759300
  14. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration.
    J Neurobiol. 2001 Nov 15;49(3):245-53 PMID: 11745662
  15. Comparison of brain metabolic activity patterns induced by ketamine, MK-801 and amphetamine in rats: support for NMDA receptor involvement in responses to subanesthetic dose of ketamine.
    Brain Res. 1999 Oct 2;843(1-2):171-83 PMID: 10528123
  16. Ketamine use, cognition and psychological wellbeing: a comparison of frequent, infrequent and ex-users with polydrug and non-using controls.
    Addiction. 2009 Jan;104(1):77-87 PMID: 19133891
  17. Specific configuration of dendritic degeneration in pyramidal neurons of the medial prefrontal cortex induced by differing corticosteroid regimens.
    Cereb Cortex. 2007 Sep;17(9):1998-2006 PMID: 17082516
  18. Chronic stress enhances synaptic plasticity due to disinhibition in the anterior cingulate cortex and induces hyper-locomotion in mice.
    Neuropharmacology. 2010 Mar-Apr;58(4-5):746-57 PMID: 20035774
  19. Spine growth in the anterior cingulate cortex is necessary for the consolidation of contextual fear memory.
    Proc Natl Acad Sci U S A. 2011 May 17;108(20):8456-60 PMID: 21531906
  20. Spine growth precedes synapse formation in the adult neocortex in vivo.
    Nat Neurosci. 2006 Sep;9(9):1117-24 PMID: 16892056
  21. Structure-stability-function relationships of dendritic spines.
    Trends Neurosci. 2003 Jul;26(7):360-8 PMID: 12850432
  22. NIH Image to ImageJ: 25 years of image analysis.
    Nat Methods. 2012 Jul;9(7):671-5 PMID: 22930834
  23. Reduced dorsal prefrontal gray matter after chronic ketamine use.
    Biol Psychiatry. 2011 Jan 1;69(1):42-8 PMID: 21035788
  24. Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders?
    Neuropsychopharmacology. 2015 Jan;40(2):259-67 PMID: 25257213
  25. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting.
    J Neurosci. 2006 Jul 26;26(30):7870-4 PMID: 16870732
  26. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex.
    Neuroscience. 2004;125(1):1-6 PMID: 15051139
  27. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex.
    Cereb Cortex. 2006 Mar;16(3):313-20 PMID: 15901656
  28. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors.
    JAMA. 2013 Aug 14;310(6):591-608 PMID: 23842577
  29. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex.
    Nature. 2002 Dec 19-26;420(6917):788-94 PMID: 12490942
  30. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists.
    Science. 2010 Aug 20;329(5994):959-64 PMID: 20724638
  31. Cytoarchitectonic and chemoarchitectonic characterization of the prefrontal cortical areas in the mouse.
    Brain Struct Funct. 2010 May;214(4):339-53 PMID: 20221886
  32. Long-term dendritic spine stability in the adult cortex.
    Nature. 2002 Dec 19-26;420(6917):812-6 PMID: 12490949
  33. Antidepressant effects of ketamine in depressed patients.
    Biol Psychiatry. 2000 Feb 15;47(4):351-4 PMID: 10686270
  34. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine.
    Neuropsychopharmacology. 2013 Oct;38(11):2268-77 PMID: 23680942
  35. Structural basis for the role of inhibition in facilitating adult brain plasticity.
    Nat Neurosci. 2011 May;14(5):587-94 PMID: 21478885
  36. Differential effects of NMDA receptor antagonism on spine density.
    Synapse. 2015 Jan;69(1):52-6 PMID: 25220437
  37. Transient effects of anesthetics on dendritic spines and filopodia in the living mouse cortex.
    Anesthesiology. 2011 Oct;115(4):718-26 PMID: 21768874
  38. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling.
    Mol Psychiatry. 2009 Aug;14(8):764-73, 739 PMID: 18982002
  39. Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo.
    Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16074-9 PMID: 21911374
  40. Optogenetic stimulation of infralimbic PFC reproduces ketamine's rapid and sustained antidepressant actions.
    Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):8106-11 PMID: 26056286
  41. Rapid enhancement of two-step wiring plasticity by estrogen and NMDA receptor activity.
    Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14650-5 PMID: 18801922
  42. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure.
    Biol Psychiatry. 2011 Apr 15;69(8):754-61 PMID: 21292242
  43. A mesoscale connectome of the mouse brain.
    Nature. 2014 Apr 10;508(7495):207-14 PMID: 24695228
  44. Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naïve and "depressed" mice exposed to chronic mild stress.
    Neuroscience. 2015 Apr 2;290:49-60 PMID: 25595985
  45. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP.
    Neuron. 2000 Oct;28(1):41-51 PMID: 11086982
  46. Chronic stress alters dendritic morphology in rat medial prefrontal cortex.
    J Neurobiol. 2004 Aug;60(2):236-48 PMID: 15266654
  47. Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses.
    Biol Psychiatry. 2013 Nov 15;74(10):742-9 PMID: 23751205
  48. Choice of cranial window type for in vivo imaging affects dendritic spine turnover in the cortex.
    Nat Neurosci. 2007 May;10(5):549-51 PMID: 17417634
  49. Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo.
    Nature. 2012 Mar 1;483(7387):92-5 PMID: 22343892
  50. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder.
    Nat Med. 2012 Sep;18(9):1413-7 PMID: 22885997
  51. Subgenual prefrontal cortex abnormalities in mood disorders.
    Nature. 1997 Apr 24;386(6627):824-7 PMID: 9126739
  52. Opposite effects of fear conditioning and extinction on dendritic spine remodelling.
    Nature. 2012 Mar 1;483(7387):87-91 PMID: 22343895
  53. Synaptic dysfunction in depression: potential therapeutic targets.
    Science. 2012 Oct 5;338(6103):68-72 PMID: 23042884
  54. Cytoarchitecture of mouse and rat cingulate cortex with human homologies.
    Brain Struct Funct. 2014 Jan;219(1):185-92 PMID: 23229151
  55. Course of improvement in depressive symptoms to a single intravenous infusion of ketamine vs add-on riluzole: results from a 4-week, double-blind, placebo-controlled study.
    Neuropsychopharmacology. 2012 May;37(6):1526-33 PMID: 22298121
  56. Sex differences in the antidepressant-like effects of ketamine.
    Neuropharmacology. 2013 Jul;70:27-34 PMID: 23337256
  57. Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver.
    Neuron. 2013 Apr 10;78(1):81-93 PMID: 23583108
  58. Whole-Brain Mapping of Neuronal Activity in the Learned Helplessness Model of Depression.
    Front Neural Circuits. 2016;10:3 PMID: 26869888
Article Info
Journal
eNeuro
Abbr.
eNeuro
ISSN
2373-2822
DOI
10.1523/ENEURO.0133-15.2016
Published
2016-00-00
Epub
2016-00-04
Language
English
Region
United States
NLM ID
101647362
PMCID
PMC4819286
Subset
IM
External Links
PubMed source DOI: 10.1523/ENEURO.0133-15.2016 PMC Full Text View journal details
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