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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Fagiolini M, Hensch TK (2000) Inhibitory threshold for critical-period activation in primary visual cortex. Nature 404(6774):183–186
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
Griffiths R, Norman RI (1993) Effects of anaesthetics on uptake, synthesis and release of transmitters. Br J Anaesth 71(1):96–107
Hara K, Harris A (2002) The anesthetic mechanism of urethane: the effects on neurotransmitter-gated ion channels. Anest Pharmacol 94(2):313–318
Hartmann M, Heumann R, Lessmann V (2001) Synaptic secretion of BDNF after high-frequency stimulation of glutamatergic synapses. EMBO J 20(21):5887–5897
Hentsch TK (2005) Critical period plasticity in local cortical circuits. Nat Rev Neurosci 6(11):877–888
Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC (2005) Theta burst stimulation of the human motor cortex. Neuron 45(2):201–206
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
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
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
Kullmann DM, Lamsa KP (2007) Long-term synaptic plasticity in hippocampal interneurons. Nat Rev Neurosci 8(9):687–699
Lewis DA, Hashimoto T, Vok DW (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6(4):312–314
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
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
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
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
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
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
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
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic, San Diego
Prince DA, Deisz RA, Thompson SM, Chagnac-Amitai Y (1992) Functional alterations in GABAergic inhibition during activity. Epilepsy Res (Suppl) 8:31–38
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
Rossini PM, Rossi S (2007) Transcranial magnetic stimulation: diagnostic, therapeutic, and research potential. Neurology 68(7):484–488
Siebner HR, Rothwell J (2003) Transcranial magnetic stimulation: new insights into representational cortical plasticity. Exp Brain Res 148(1):1–16
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
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
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
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
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
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
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
Tsumoto T (1992) Long-term potentiation and long-term depression in the neocortex. Prog Neurobiol 39(2):209–228
Wang H, Wang X, Scheich H (1996) LTD and LTP induced by transcranial magnetic stimulation in auditory cortex. NeuroReport 7(2):521–525
Wei J, Wu JY (2008) Post-translational regulation of L-glutamic acid decarboxylase in the brain. Neurochem Res 33(8):1459–1465
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
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
Corresponding author
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-009-1961-8