GABA_A receptor subtype specific enhancement of inhibition in human motor cortex

Abstract

Inhibition is of fundamental importance to regulate activity in cortical circuits. Inhibition is mediated through a diversity of different interneurones and γ-aminobutyric acid A receptor (GABA A R) subtypes. Here we employed paired-pulse transcranial magnetic stimulation (TMS) to measure short interval intracortical inhibition (SICI), a GABA A R-mediated inhibition in human motor cortex, to address the question of which GABA A R subtype is responsible for this form of inhibition. It has been shown that classical benzodiazepines (diazepam and lorazepam) have a non-selective affinity profile at different α-subunit-bearing subtypes of the GABA A R while zolpidem has a 10-fold greater affinity to the α1-subunit-bearing GABA A R compared with those bearing the α2-or α3-subunit. We found that, in seven healthy subjects, a single oral dose of 20 mg of diazepam or 2.5 mg of lorazepam significantly increased SICI, whereas 10 mg of zolpidem did not change SICI. This dissociation occurred despite equal sedation by all three drugs, an α1-subunit GABA A R-mediated effect. The findings strongly suggest that SICI is not mediated by the α1-subunit-bearing subtype of the GABA A R but by those bearing either the α2-or α3-subunit. This study represents an attempt by means of TMS to identify GABA A R subtype-specific action at the systems level of human cortex, a highly relevant issue because the different α-subunit-bearing subtypes of the GABA A R are differently involved in benzodiazepine-mediated effects such as sedation, amnesia or anxiolysis, in developmental cortical plasticity, and in neurological disorders such as epilepsy.

Preconditioning tDCS facilitates subsequent tDCS effect on skill acquisition in older adults

“…More specifically, the following formula was used, ∑ 20( + ) 2 , where a and b represent MEP amplitudes at consecutive stimulus intensities, e.g., 90% rMT and 110% rMT. We also used short-latency intracortical inhibition (SICI) to assess GABAA receptor (Di Lazzaro et al 2006) mediated intracortical inhibition and glutamatergic and intracortical facilitation (ICF) to examine N-methyl-Daspartate (NMDA) receptor mediated intracortical facilitation (Ziemann et al 1998). For the assessment of SICI and ICF, two Magstim units were configured to deliver paired pulse stimulation with an interstimulus interval (ISI) of 3 ms and 13 ms, respectively (Kossev et al 2003, Kujirai et al 1993).…”

“…The current study also examined SICI and ICF to elucidate changes in GABAA (Di Lazzaro et al 2006) and glutamatergic N-methyl-D-aspartate (NMDA) receptors (Ziemann et al 1998) following tDCS/motor learning, respectively. A magnetic resonance spectroscopy study by Stagg and colleagues (2011a) revealed that tDCS (1mA, 10min) with the anode placed over M1 reduces local GABA concentration and tDCS with the cathode placed over M1reduces glutamatergic activity.…”

Motor cortex inhibition

“…23 This finding may be important for refining cortical signals involved in the accurate selection and control of motor responses. Because in healthy adults SICI is upregulated by both dopaminergic agonists 24 and GABA A agonists 22 and because psychostimulants also alter SICI (although in complex ways influenced possibly by age, dose, diagnosis, and genetic factors), we speculate that SICI may provide a window into further investigations to the role of both GABA and GABA/ dopamine interactions in frontal cortex behavioral and motor dysfunction in ADHD. Studies of SICI in healthy adults suggest that this may be relevant to motor task inhibition 25 and reward expectation.…”

“…21 SICI is believed to result from ␥-aminobutyric acid (GABA) A -mediated inhibition at the level of the primary motor cortex. 22 The surround inhibition produced by GABAergic interneurons and modulated by dopamine is believed to provide an increased signal-to-noise ratio in the frontal cortex. 23 This finding may be important for refining cortical signals involved in the accurate selection and control of motor responses.…”

Modulation of Proprioceptive Integration in the Motor Cortex Shapes Human Motor Learning

“…Integration of proprioceptive input in the motor cortex can be measured using a paired-pulse transcranial magnetic stimulation (TMS) paradigm to test GABA A ergic intracortical inhibition (Kujirai et al, 1993;Ziemann et al, 1996;Ilić et al, 2002;Rosenkranz and Rothwell, 2003;Di Lazzaro et al, 2006;Florian et al, 2008). This is performed either alone or during muscle spindle Ia-afferent input evoked from the resting target muscle by lowamplitude vibration (Burke et al, 1976;Roll et al, 1989).…”