Skip to main content
SpringerLink
Log in

Theta burst and conventional low-frequency rTMS differentially affect GABAergic neurotransmission in the rat cortex

  • Research Article
  • Published:
Experimental Brain Research Aims and scope Submit manuscript

Abstract

Modified cortical excitability following repetitive transcranial magnetic stimulation (rTMS) may be related to short- or long-term synaptic plasticity of neuronal excitation but could also affect cortical inhibition. Therefore, in the rat we tested how three different rTMS protocols, intermittent and continuous theta-burst (iTBS, cTBS), and low-frequency 1 Hz stimulation, change the expression of GAD65, GAD67 and GAT-1 which are expressed in cortical inhibitory interneurons in an activity-dependent manner. Acutely (2 h), all protocols reduced the expression of GAD67 in frontal, motor, somatosensory and visual cortex but increased that of GAD65 and GAT-1 to different degree, with iTBS having the strongest acute effect. The initial decrease in GAD67 reversed after 1 day, leading to a strong increase in GAD67 expression for up to 7 days primarily in the frontal cortex in case of iTBS, cTBS and in all studied areas following 1 Hz rTMS. While also GAD65 and GAT-1 expression reversed after 1 day in case of iTBS and cTBS, 1 Hz rTMS induced a steady increase in GAD65 and GAT-1 expression during the 7 days investigated. Our data demonstrate that rTMS affects the expression of activity-dependent proteins of the cortical inhibitory interneurons. Besides common effects of low- (1 Hz) and high-frequency (TBS) stimulation on protein expression, differences in quantity and time course of changes point to differences in the contribution of possible neuronal subsystems. Further studies are needed to distinguish cell-type specific effects.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Aydin-Abidin S, Trippe J, Funke K, Eysel UT, Benali A (2008) High- and low-frequency repetitive transcranial magnetic stimulation differentially activates c-Fos and zif268 protein expression in the rat brain. Exp Brain Res 188(2):249–261

    Article  CAS  PubMed  Google Scholar 

  • Benali A, Leefken I, Eysel UT, Weiler E (2003) A computerized image analysis system for quantitative analysis of cells in histological brain sections. J Neurosci Meth 125(1–2):33–43

    Article  Google Scholar 

  • Benali A, Weiler E, Benali Y, Dinse HR, Eysel UT (2008) Excitation and inhibition jointly regulate cortical reorganization in adult rats. J Neurosci 28(47):12284–12293

    Article  CAS  PubMed  Google Scholar 

  • Benson DL, Huntsman MM, Jones EG (1994) Activity-dependent changes in GAD and preprotachykinin mRNAs in visual cortex of adult monkeys. Cereb Cortex 4(1):40–51

    Article  CAS  PubMed  Google Scholar 

  • Bergado-Acosta JR, Sangha S, Narayanan RT, Obata K, Pape HC, Stork O (2008) Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory. Learn Mem 15(3):163–171

    Article  CAS  PubMed  Google Scholar 

  • Bliss TV, Lomo T (1973) Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232(2):331–356

    CAS  PubMed  Google Scholar 

  • Caputi A, Rozov A, Blatow M, Monyer H (2008) Two calretinin-positive GABAergic cell types in layer 2/3 of the mouse neocortex provide different forms of inhibition. Cerebr Cortex 19(6):1345–1359

    Article  Google Scholar 

  • Chaudhuri A, Nissanov J, Larocque S, Rioux L (1997) Dual activity maps in primate visual cortex produced by different temporal patterns of zif268 mRNA and protein expression. PNAS 94(6):2671–2675

    Article  CAS  PubMed  Google Scholar 

  • Clement EA, Richard A, Thwaites M, Ailon J, Peters S, Dickson CT (2008) Cyclic and sleep-like spontaneous alternations of brain state under urethane anaesthesia. PLoS ONE 3(4):e2004

    Article  PubMed  Google Scholar 

  • de Graaf R, Mason G, Patel A, Behar KL, Rothman DL (2003) In vivo 1H-[13C]-NMR spectroscopy of cerebral metabolism. NMR Biomed 16(6–7):339–357

    Article  PubMed  Google Scholar 

  • Di Lazzaro V, Pilato F, Saturno E, Oliviero A, Dileone M, Mazzone P, Insola A, Tonali PA, Ranieri F, Huang YZ, Rothwell JC (2005) Theta-burst repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex. J Physiol 565(3):945–950

    Article  PubMed  Google Scholar 

  • Di Lazzaro V, Pilato F, Dileone M, Profice P, Oliviero A, Mazzone P, Insola A, Ranieri F, Meglio M, Tonali PA, Rothwell JC (2008) The physiological basis of the effects of intermittent theta burst stimulation of the human motor cortex. J Physiol 586(16):3871–3879

    Article  PubMed  Google Scholar 

  • Esclapez M, Tillakaratne NJ, Kaufman DL, Tobin AJ, Houser CR (1994) Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms. J Neurosci 14(3):1834–1855

    CAS  PubMed  Google Scholar 

  • Esser SK, Huber R, Massimini M, Peterson MJ, Ferrarelli F, Tononi G (2006) A direct demonstration of cortical LTP in humans: a combined TMS/EEG study. Brain Res Bull 69(1):86–94

    Article  CAS  PubMed  Google Scholar 

  • Fagiolini M, Hensch TK (2000) Inhibitory threshold for critical-period activation in primary visual cortex. Nature 404(6774):183–186

    Article  CAS  PubMed  Google Scholar 

  • Greif KF, Tillakaratne NJ, Erlander MG, Feldblum S, Tobin AJ (1992) Transient increase in expression of a glutamate decarboxylase (GAD) mRNA during the postnatal development of the rat striatum. Dev Biol 153(1):158–164

    Article  CAS  PubMed  Google Scholar 

  • Griffiths R, Norman RI (1993) Effects of anaesthetics on uptake, synthesis and release of transmitters. Br J Anaesth 71(1):96–107

    Article  CAS  PubMed  Google Scholar 

  • Hara K, Harris A (2002) The anesthetic mechanism of urethane: the effects on neurotransmitter-gated ion channels. Anest Pharmacol 94(2):313–318

    CAS  Google Scholar 

  • Hartmann M, Heumann R, Lessmann V (2001) Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J 20(21):5887–5897

    Article  CAS  PubMed  Google Scholar 

  • Hentsch TK (2005) Critical period plasticity in local cortical circuits. Nat Rev Neurosci 6(11):877–888

    Article  Google Scholar 

  • Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC (2005) Theta burst stimulation of the human motor cortex. Neuron 45(2):201–206

    Article  CAS  PubMed  Google Scholar 

  • Jiang B, Kitamura A, Yasuda H, Sohya K, Maruyama A, Yanagawa Y, Obata K, Tsumoto T (2004) Brain-derived neurotrophic factor acutely depresses excitatory synaptic transmission to GABAergic neurons in visual cortical slices. Eur J Neurosci 20(3):709–718

    Article  PubMed  Google Scholar 

  • Jones MW, Errington ML, French PJ, Fine A, Bliss TV, Garel S, Charnay P, Bozon B, Laroche S, Davis S (2001) A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat Neurosci 4(3):289–296

    Article  CAS  PubMed  Google Scholar 

  • Kang TC, Kim HS, Seo MO, Choi SY, Kwon OS, Baek NI, Lee HY, Won MH (2001) The temporal alteration of GAD67/GAD65 ratio in the gerbil hippocampal complex following seizure. Brain Res 920(1–2):159–169

    Article  CAS  PubMed  Google Scholar 

  • Kullmann DM, Lamsa KP (2007) Long-term synaptic plasticity in hippocampal interneurons. Nat Rev Neurosci 8(9):687–699

    Article  CAS  PubMed  Google Scholar 

  • Lewis DA, Hashimoto T, Vok DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6(4):312–314

    Article  CAS  PubMed  Google Scholar 

  • Liang F, Jones EG (1997a) Differential and time-dependent changes in gene expression for type II calcium/calmodulin-dependent protein kinase, 67 kDa glutamic acid decarboxylase, and glutamate receptor subunits in tetanus toxin-induced focal epilepsy. J Neurosci 17(6):2168–2180

    CAS  PubMed  Google Scholar 

  • Liang F, Jones EG (1997b) Zif268 and Fos-like immunoreactivity in tetanus toxin-induced epilepsy: reciprocal changes in the epileptic focus and the surround. Brain Res 778(2):281–292

    Article  CAS  PubMed  Google Scholar 

  • López-Bendito G, Sturgess K, Erdélyi F, Szabo G, Molnár Z, Paulsen O (2004) Preferential origin and layer destination of GAD65-GFP cortical interneurons. Cerebr Cortex 14:1122–1133

    Article  Google Scholar 

  • Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C (2004) Interneurons of the neocortical inhibitory system. Nat Rev Neurosci 5(10):793–807

    Article  CAS  PubMed  Google Scholar 

  • Michaluk J, Antkiewicz-Michaluk L, Vetulani J (2001) Conditions of application of repeated transcranial magnetic stimulation to rats may mask the effects of the treatment. Pol J Pharmacol 53(6):685–687

    CAS  PubMed  Google Scholar 

  • Minchin MC (1981) The effect of anaesthetics on the uptake and release of gamma-aminobutyrate and D-aspartate in rat brain slices. Brit J Pharmacol 73(3):681–689

    CAS  Google Scholar 

  • Patel AB, de Graaf RA, Martin DL, Battaglioli G, Behar KL (2006) Evidence that GAD65 mediates increased GABA synthesis during intense neuronal activity in vivo. J Neurochem 97(2):385–396

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, San Diego

    Google Scholar 

  • Prince DA, Deisz RA, Thompson SM, Chagnac-Amitai Y (1992) Functional alterations in GABAergic inhibition during activity. Epilepsy Res (Suppl) 8:31–38

    CAS  Google Scholar 

  • Rees VH, Laurence DJ (1955) The correspondence with Beer’s law for the optical density of stained protein patterns on filter paper as a function of surface protein concentration. Clin Chem 1(5):329–344

    CAS  PubMed  Google Scholar 

  • Rossini PM, Rossi S (2007) Transcranial magnetic stimulation: diagnostic, therapeutic, and research potential. Neurology 68(7):484–488

    Article  PubMed  Google Scholar 

  • Siebner HR, Rothwell J (2003) Transcranial magnetic stimulation: new insights into representational cortical plasticity. Exp Brain Res 148(1):1–16

    Article  PubMed  Google Scholar 

  • Sinclair MD (2003) A review of the physiological effects of alpha2-agonists related to the clinical use of medetomidine in small animal practice. Can Vet J 44(11):885–897

    CAS  PubMed  Google Scholar 

  • Stagg CJ, Wylezinska M, Matthews PM, Johansen-Berg H, Jezzard P, Rothwell JC, Bestmann S (2009) Neurochemical effects of theta burst stimulation as assessed by magnetic resonance spectroscopy. J Neurophysiol 101(6):2872–2877

    Article  CAS  PubMed  Google Scholar 

  • Sun QQ, Zhang Z, Jiao Y, Zhang C, Szabó G, Erdélyi F (2009) Differential metabotropic glutamate receptor expression and modulation in two neocortical inhibitory networks. J Neurophysiol 101(5):2679–2692

    Article  CAS  PubMed  Google Scholar 

  • Teo JT, Terranova C, Swayne O, Greenwood RJ, Rothwell JC (2009) Differing effects of intracortical circuits on plasticity. Exp Brain Res 193(4):555–563

    Article  CAS  PubMed  Google Scholar 

  • Touge T, Gerschlager W, Brown P, Rothwell JC (2001) Are the after-effects of low-frequency rTMS on motor cortex excitability due to changes in the efficacy of cortical synapses. Clin Neurophysiol 112(11):2138–2145

    Article  CAS  PubMed  Google Scholar 

  • Trippe J, Benali A, Weiler E, Mix A, Funke K (2008) Chronic reduction of parvalbumin expression in rat cortex following treatment with high-frequency intermittend theta-burst repetitive transcranial magnetic stimulation. FENS Abstr 6:122.18

    Google Scholar 

  • Tropea D, Kreiman G, Lyckman A, Mukherjee S, Yu H, Horng S, Sur M (2006) Gene expression changes and molecular pathways mediating activity-dependent plasticity in visual cortex. Nat Neurosci 9(5):660–668

    Article  CAS  PubMed  Google Scholar 

  • Tsumoto T (1992) Long-term potentiation and long-term depression in the neocortex. Prog Neurobiol 39(2):209–228

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Wang X, Scheich H (1996) LTD and LTP induced by transcranial magnetic stimulation in auditory cortex. NeuroReport 7(2):521–525

    Article  CAS  PubMed  Google Scholar 

  • Wei J, Wu JY (2008) Post-translational regulation of L-glutamic acid decarboxylase in the brain. Neurochem Res 33(8):1459–1465

    Article  CAS  PubMed  Google Scholar 

  • Wei J, Davis KM, Wu H, Wu JY (2004) Protein phosphorylation of human brain glutamic acid decarboxylase (GAD)65 and GAD67 and its physiological implications. Biochemistry 43(20):6182–6189

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We like to thank Ute Neubacher, Dimitrula Winkler, Gabriele Bomholt and Angelika Herker-See for the excellent assistance in animal handling and histological procedures. This study had been supported by grants of the Deutsche Forschungsgemeinschaft to K.F. (DFG, FU 256/2-1 and SFB 509 TP C12).

Author information

Authors and Affiliations

  1. Department of Neurophysiology, Medical Faculty, Ruhr-University Bochum, 44780, Bochum, Germany

    Jörn Trippe, Annika Mix, Selcen Aydin-Abidin, Klaus Funke & Alia Benali

Authors
  1. Jörn Trippe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annika Mix
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Selcen Aydin-Abidin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Klaus Funke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alia Benali
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Klaus Funke.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Trippe, J., Mix, A., Aydin-Abidin, S. et al. Theta burst and conventional low-frequency rTMS differentially affect GABAergic neurotransmission in the rat cortex. Exp Brain Res 199, 411–421 (2009). https://doi.org/10.1007/s00221-009-1961-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00221-009-1961-8

Keywords

Search

Navigation