Abstract
Modulation of human cortical excitability by repetitive transcranial magnetic stimulation (rTMS) appears to be in part related to changed activity of inhibitory systems. Our own studies showed that intermittent theta-burst stimulation (iTBS) applied via rTMS to rat cortex primarily affects the parvalbumin-expressing (PV) fast-spiking interneurons (FSIs), evident via a strongly reduced PV expression. We further found the iTBS effect on PV to be age-dependent since no reduction in PV could be induced before the perineuronal nets (PNNs) of FSIs start to grow around postnatal day (PD) 30. To elucidate possible iTBS-induced changes in the electrical properties of FSIs and cortical network activity during cortical critical period, we performed ex vivo—in vitro whole-cell patch clamp recordings from pre-labeled FSIs in the current study. FSIs of verum iTBS-treated rats displayed a higher excitability than sham-treated controls at PD29–38, evident as higher rates of induced action potential firing at low current injections (100–200 pA) and a more depolarized resting membrane potential. This effect was absent in younger (PD26–28) and older animals (PD40–62). Slices of verum iTBS-treated rats further showed higher rates of spontaneous excitatory postsynaptic currents (sEPSCs). Based on these and previous findings we conclude that FSIs are particularly sensitive to TBS during early cortical development, when FSIs show an activity-driven step of maturation which is paralleled by intense growth of the PNNs and subsequent closure of the cortical critical period. Although to be proven further, rTMS may be a possible early intervention to compensate for hypo-activity related mal-development of cortical neuronal circuits.
Highlights
Due to its modulatory action on human cortical excitability, repetitive transcranial magnetic stimulation has become a promising tool for the treatment of psychiatric and neurodegenerative disorders and cortical reorganization after stroke (Di Lazzaro et al, 2008a; Grefkes et al, 2010; Fitzgerald, 2011; for review, see Lefaucheur et al, 2014)
We found no indications of reduced activity in fast-spiking interneurons (FSIs) after intermittent theta-burst stimulation (iTBS) but an increased excitability to weak depolarizing stimuli
We found partly opposite effects of iTBS and cTBS in our rat studies on neuronal activity marker expression (Trippe et al, 2009; Benali et al, 2011) and learning performance (Mix et al, 2010), we found a clear strain-dependent variation especially of the cTBS effect (Mix et al, 2014)
Summary
Due to its modulatory action on human cortical excitability, repetitive transcranial magnetic stimulation (rTMS) has become a promising tool for the treatment of psychiatric and neurodegenerative disorders and cortical reorganization after stroke (Di Lazzaro et al, 2008a; Grefkes et al, 2010; Fitzgerald, 2011; for review, see Lefaucheur et al, 2014). Besides possible induction of long-term depression (LTD)- and long-term potential (LTP)-like changes in cortical synaptic connectivity directly induced by low- and high-frequency stimulation protocols (Thickbroom, 2007), a modulation of the activity of inhibitory cortical systems has been discussed on the basis of human data (Di Lazzaro et al, 2008b; Rogasch et al, 2014). By applying different rTMS protocols to rats, we could recently show that neuronal activity markers related to GABAergic neurons, like the 67 kD isoform of GABA synthesizing enzyme glutamic acid decarboxylase (GAD67) and the calcium-binding proteins parvalbumin (PV) and calbindin expressed in different classes of inhibitory interneurons (Kawaguchi and Kubota, 1998; Kawaguchi and Kondo, 2002; Markram et al, 2004), are differently affected by low- (1 Hz) and high-frequency (iTBS, cTBS) protocols and that the iTBS protocol induces a strong and reliable reduction in the number of cells expressing PV within about 30 min (Trippe et al, 2009; Benali et al, 2011; Hoppenrath and Funke, 2013; Volz et al, 2013; Mix et al, 2014)
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