Understanding the effects of the N-methyl-D-aspartate receptor (NMDA-R) antagonist ketamine on brain function is of considerable interest due to the discovery of its fast-acting antidepressant properties. It is well known that gamma oscillations are increased when ketamine is administered to rodents and humans, and increases in the auditory steady-state response (ASSR) have also been observed.
Aims:
To elucidate the cellular substrate of the increase in network activity and synchrony observed by sub-anesthetic doses of ketamine, the aim was to investigate spike timing and regularity and determine how this is affected by the animal’s motor state.
Methods:
Single unit activity and local field potentials from the auditory cortex of awake, freely moving rats were recorded with microelectrode arrays during an ASSR paradigm.
Results:
Ketamine administration yielded a significant increase in ASSR power and phase locking, both significantly modulated by motor activity. Before drug administration, putative fast-spiking interneurons (FSIs) were significantly more entrained to the stimulus than putative pyramidal neurons (PYRs). The degree of entrainment significantly increased at lower doses of ketamine (3 and 10 mg/kg for FSIs, 10 mg/kg for PYRs). At the highest dose (30 mg/kg), a strong increase in tonic firing of PYRs was observed.
Conclusions:
These findings suggest an involvement of FSIs in the increased network synchrony and provide a possible cellular explanation for the well-documented effects of ketamine-induced increase in power and synchronicity during ASSR. The results support the importance to evaluate different motor states separately for more translational preclinical research.
AbdallahCGDuttaAAverillCL, et al. (2018) Ketamine, but Not the NMDAR antagonist lanicemine, increases prefrontal global connectivity in depressed patients. Chronic Stress2: 2470547018796102.
2.
Amat-ForasterMCeladaPRichterU, et al. (2019) Modulation of thalamo-cortical activity by the NMDA receptor antagonists ketamine and phencyclidine in the awake freely-moving rat. Neuropharmacology158: 107745.
3.
Amat-ForasterMJensenAAPlathN, et al. (2018) Temporally dissociable effects of ketamine on neuronal discharge and gamma oscillations in rat thalamo-cortical networks. Neuropharmacology137: 13–23.
4.
BarthóPHiraseHMonconduitL, et al. (2004) Characterization of neocortical principal cells and interneurons by network interactions and extracellular features. J Neurophysiol92(1): 600–608.
5.
BerensP (2009) CircStat: A Matlab toolbox for circular statistics. J Stat Soft31(10): 1–21.
6.
BermanRMCappielloAAnandA, et al. (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry47(4): 351–354.
7.
BowmanCRichterUJonesCR, et al. (2022). Activity-state dependent reversal of ketamine-induced resting state EEG effects by clozapine and naltrexone in the freely moving rat. Front Psychiatry13: 737295.
8.
BrzoskoZMierauSBPaulsenO (2019) Neuromodulation of spike-timing-dependent plasticity: Past, present, and future. Neuron103(4): 563–581.
9.
CaddyCGiaroliGWhiteTP, et al. (2014) Ketamine as the prototype glutamatergic antidepressant: Pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Ther Adv Psychopharmacol4(2): 75–99.
10.
CarlénMMeletisKSiegleJH, et al. (2012) A critical role for NMDA receptors in parvalbumin interneurons for gamma rhythm induction and behavior. Mol Psychiatry17(5): 537–548.
11.
De la SalleSChoueiryJShahD, et al. (2016) Effects of ketamine on resting-state EEG activity and their relationship to perceptual/dissociative symptoms in healthy humans. Front Pharmacol7: 348.
12.
DeFelipeJLópez-CruzPLBenavides-PiccioneR, et al. (2013) New insights into the classification and nomenclature of cortical GABAergic interneurons. Nat Rev Neurosci14(3): 202–216.
13.
FDA (2019) Press Announcements – FDA Approves New Nasal Spray Medication for Treatment-Resistant Depression; Available Only at a Certified Doctor’s Office or Clinic. Office of the Commissioner. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632761 (Accessed 20 October 2022).
14.
FeldmanDE (2012) The spike-timing dependence of plasticity. Neuron75(4): 556–571.
15.
FitzgeraldPJWatsonBO (2019) In vivo electrophysiological recordings of the effects of antidepressant drugs. Exp Brain Res237(7): 1593–1614.
16.
FuruyaROkaKWatanabeI, et al. (1999). The effects of ketamine and propofol on neuronal nicotinic acetylcholine receptors and P2x purinoceptors in PC12 cells. Anesth Anal88(1): 174–180.
17.
GalambosRMakeigSTalmachoffPJ (1981) A 40-Hz auditory potential recorded from the human scalp. Proc Natl Acad Sci78(4): 2643–2647.
18.
GastambideFMitchellSNRobbinsT W, et al. (2013) Temporally distinct cognitive effects following acute administration of ketamine and phencyclidine in the rat. Eur Neuropsychopharmacol23(11): 1414–1422.
GhimireMCaiRLingL, et al. (2020). Nicotinic receptor subunit distribution in auditory cortex: Impact of aging on receptor number and function. J Neurosci40(30): 5724–5739.
21.
Gonzalez-BurgosGLewisDA (2008) GABA neurons and the mechanisms of network oscillations: Implications for understanding cortical dysfunction in schizophrenia. Schizophr Bull34(5): 944–961.
22.
Grent-‘t-JongTRivoltaDGrossJ, et al. (2018) Acute ketamine dysregulates task-related gamma-band oscillations in thalamo-cortical circuits in schizophrenia. Brain141(8): 2511–2526.
23.
HaafMLeichtGCuricS, et al. (2018) Glutamatergic deficits in schizophrenia – Biomarkers and pharmacological interventions within the ketamine model. Curr Pharm Biotechnol19(4): 293–307.
24.
HakamiTJonesNCTolmachevaEA, et al. (2009) NMDA receptor hypofunction leads to generalized and persistent aberrant γ oscillations independent of hyperlocomotion and the state of consciousness. PLoS One4(8): e6755.
25.
HansenIHAgerskovCArvastsonL, et al. (2019) Pharmaco-electroencephalographic responses in the rat differ between active and inactive locomotor states. Eur J Neurosci50(2): 1948–1971.
26.
HerrerasO (2016) Local field potentials: Myths and misunderstandings. Front Neural Circuits10: 101.
27.
HiyoshiTKambeDKarasawaJI, et al. (2014) Differential effects of NMDA receptor antagonists at lower and higher doses on basal gamma band oscillation power in rat cortical electroencephalograms. Neuropharmacology85: 384–396.
28.
HomayounHMoghaddamB (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci27(43): 11496–11500.
29.
HuntMJAdamsNEŚredniawaW, et al. (2019) The olfactory bulb is a source of high-frequency oscillations (130–180 Hz) associated with a subanesthetic dose of ketamine in rodents. Neuropsychopharmacology44(2): 435–442.
30.
HuntMJFalinskaMŁeskiS, et al. (2011) Differential effects produced by ketamine on oscillatory activity recorded in the rat hippocampus, dorsal striatum and nucleus accumbens. J Psychopharmacol (Oxford, England)25(6): 808–821.
31.
HuntMJRaynaudBGarciaR (2006) Ketamine dose-dependently induces high-frequency oscillations in the nucleus accumbens in freely moving rats. Biol Psychiatry60(11): 1206–1214.
32.
JacksonMEHomayounHMoghaddamB (2004) NMDA receptor hypofunction produces concomitant firing rate potentiation and burst activity reduction in the prefrontal cortex. Proc Natl Acad Sc101(22): 8467–8472.
33.
KhlestovaEJohnsonJWKrystalJH, et al. (2016) The role of GluN2C-containing NMDA receptors in ketamine’s psychotogenic action and in schizophrenia models. J Neurosci36(44): 11151–11157.
34.
KimHÄhrlund-RichterSWangX, et al. (2016) Prefrontal parvalbumin neurons in control of attention. Cell164(1–2): 208–218.
35.
KinneyJW (2006) A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J Neurosci26(5): 1604–1615.
36.
KissTHoffmannWEScottL, et al. (2011) Role of thalamic projection in NMDA receptor-induced disruption of cortical slow oscillation and short-term plasticity. Front Psychiatry2: 14.
37.
KittelbergerKHurEESazegarS, et al. (2012). Comparison of the effects of acute and chronic administration of ketamine on hippocampal oscillations: Relevance for the NMDA receptor hypofunction model of schizophrenia. Brain Struct Func217(2): 395–409.
38.
KotermanskiSEJohnsonJW (2009) Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer’s drug memantine. J Neurosci29(9): 2774–2779.
39.
KozonoNHondaSTadaM, et al. (2019) Auditory steady state response; nature and utility as a translational science tool. Sci Rep9(1): 8454.
40.
KwonJSO’DonnellBFWallensteinG V, et al. (1999) Gamma frequency-range abnormalities to auditory stimulation in schizophrenia. Arch Gen Psychiatry56(11): 1001–1005. Available at: http://www.ncbi.nlm.nih.gov/pubmed/10565499(Accessed 20 October 2022).
41.
LittlewoodCLCashDDixonAL, et al. (2006) Using the BOLD MR signal to differentiate the stereoisomers of ketamine in the rat. NeuroImage32(4): 1733–1746.
42.
MaLSkoblenickKSeamansJK, et al. (2015) Ketamine-induced changes in the signal and noise of rule representation in working memory by lateral prefrontal neurons. J Neurosci35(33): 11612–11622.
43.
MealingGALanthornTHMurrayCL, et al. (1999). Differences in degree of trapping of low-affinity uncompetitive N-methyl-D-aspartic acid receptor antagonists with similar kinetics of block. J Pharmacol Exp Ther288(1): 204–210.
44.
MionGVillevieilleT (2013) Ketamine pharmacology: An update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther19: 370–380.
45.
MaxwellCREhrlichmanRSLiangY, et al. (2006) Ketamine produces lasting disruptions in encoding of sensory stimuli. J Pharmacol Exp Ther316(1): 315–24.
46.
McNallyJMMcCarleyRW (2016) Gamma band oscillations. Curr Opin Psychiatry29(3): 202–210.
47.
NakaoKNakazawaK (2014) Brain state-dependent abnormal LFP activity in the auditory cortex of a schizophrenia mouse model. Front Neurosci8: 168.
48.
NicolásMJLópez-AzcárateJValenciaM, et al. (2011) Ketamine-induced oscillations in the motor circuit of the rat basal ganglia. PLoS One6(7): e21814.
49.
PachitariuMSteinmetzNKadirS, et al. (2016) Fast and accurate spike sorting of high-channel count probes with KiloSort. In: LeeDDSugiyamaMLuxburg, et al. (eds) Advances in Neural Information Processing Systems 29 (NIPS 2016). Barcelona, Spain: NIPS Proceedings.
50.
PastorMAArtiedaJArbizuJ, et al. (2002) Activation of human cerebral and cerebellar cortex by auditory stimulation at 40 Hz. J Neurosci22(23): 10501–10506. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12451150 (accessed 23 July 2019).
51.
PaxinosGWatsonC (2007) The Rat Brain in Stereotaxic Coordinates.London: Academic Press.
52.
PlourdeGBaribeauJBonhommeV (1997) Ketamine increases the amplitude of the 40-Hz auditory steady-state response in humans. Br J Anaesth78(5): 524–529.
53.
PoppSBehlBJoshiJJ, et al. (2016) In search of the mechanisms of ketamine’s antidepressant effects: How robust is the evidence behind the mTor activation hypothesis. 1000Research5: 634.
54.
PurvesDAugustineGJFitzpatrickD, et al. (2001) An overview of cortical structure. Sinauer Associates. Available at: https://www.ncbi.nlm.nih.gov/books/NBK10870/ (Accessed 20 October 2022).
55.
RadfordKDParkTYLeeBH, et al. (2017) Dose-response characteristics of intravenous ketamine on dissociative stereotypy, locomotion, sensorimotor gating, and nociception in male Sprague-Dawley rats. Pharmacol Biochem Behav153: 130–140.
56.
ShafferCLOsgoodSMSmithDL, et al. (2014) Enhancing ketamine translational pharmacology via receptor occupancy normalization. Neuropharmacology86: 174–180.
57.
ShenGHanFShiW-X (2018) Effects of low doses of ketamine on pyramidal neurons in rat prefrontal cortex. Neuroscience384: 178–187.
58.
ShinY-WO’DonnellBFYounS, et al. (2011) Gamma oscillation in schizophrenia. Psychiatry Investigation8(4): 288–296.
59.
SivaraoDV. (2015) The 40-Hz auditory steady-state response: A selective biomarker for cortical NMDA function. Ann N Y Acad Sci1344(1): 27–36.
60.
SivaraoDVChenPSenapatiA, et al. (2016) 40 Hz auditory steady-state response is a pharmacodynamic biomarker for cortical NMDA receptors. Neuropsychopharmacology41(9): 2232–2240.
61.
StandaertDGLandwehrmeyerGBKernerJA, et al. (1996) Expression of NMDAR2D glutamate receptor subunit mRNA in neurochemically identified interneurons in the rat neostriatum, neocortex and hippocampus. Brain Res. Mol Brain Res42(1): 89–102. Available at: http://www.ncbi.nlm.nih.gov/pubmed/8915584 (Accessed 20 October 2022).
62.
StarkEEichlerRRouxL, et al. (2013) Inhibition-induced theta resonance in cortical circuits. Neuron80(5): 1263–1276.
63.
VohsJLChambersRAO’DonnellBF, et al. (2012) Auditory steady state responses in a schizophrenia rat model probed by excitatory/inhibitory receptor manipulation. Int J Psychophysiol86(2): 136–142.
64.
VollenweiderFXGeyerMA (2001). A systems model of altered consciousness: Integrating natural and drug-induced psychoses. Brain Res Bull56(5): 495507.
65.
WilsonFJLeiserSCIvarssonM, et al. (2014) Can pharmaco-electroencephalography help improve survival of central nervous system drugs in early clinical development?Drug Discov Today19(3): 282–288.
66.
XiDZhangWWangH-X, et al. (2009) Dizocilpine (MK-801) induces distinct changes of N-methyl-D-aspartic acid receptor subunits in parvalbumin-containing interneurons in young adult rat prefrontal cortex. Int J Neuropsychopharmacol12(10): 1395–1408.
67.
ZanosPMoaddelRMorrisPJ, et al. (2018) Ketamine and ketamine metabolite pharmacology: Insights into therapeutic mechanisms. Pharmacol Rev70(3): 621–660.
68.
ZhouT-HMuellerNESpencerKM, et al. (2018) Auditory steady state response deficits are associated with symptom severity and poor functioning in patients with psychotic disorder. Schizophr Res201: 278–286.
69.
ZickJLBlackmanRKCroweDA, et al. (2018) Blocking NMDAR disrupts spike timing and decouples monkey prefrontal circuits: Implications for activity-dependent disconnection in schizophrenia. Neuron98(6): 1243–1255.e5.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
