Tiagabine induced modulation of oscillatory connectivity and activity match PET-derived, canonical GABA-A receptor distributions

As the most abundant inhibitory neurotransmitter in the mammalian brain, gamma-aminobutyric acid (GABA) plays a crucial role in shaping the frequency and amplitude of oscillations, which suggests a role for GABA in shaping the topography of functional connectivity and activity. This study explored the effects of pharmacologically blocking the reuptake of GABA (increasing local concentrations) using the GABA transporter 1 (GAT1) blocker, tiagabine (15 mg). In a placebo-controlled crossover design, we collected resting magnetoencephalography (MEG) recordings from 15 healthy individuals prior to, and at 1-, 3- and 5- hours post, administration of tiagabine and placebo. We quantified whole brain activity and functional connectivity in discrete frequency bands. Drug-by-session (2 x 4) analysis of variance in connectivity revealed interaction and main effects. Post-hoc permutation testing of each post-drug recording vs. respective pre-drug baseline revealed consistent reductions of a bilateral occipital network spanning theta, alpha and beta frequencies, across 1- 3- and 5- hour recordings following tiagabine only. The same analysis applied to activity revealed significant increases across frontal regions, coupled with reductions in posterior regions, across delta, theta, alpha and beta frequencies. Crucially, the spatial distribution of tiagabine-induced changes overlap with group-averaged maps of the distribution of GABA(A) receptors, from flumazenil (FMZ-V-T) PET, demonstrating a link between GABA availability, GABA(A) receptor distribution, and low-frequency network oscillations. Our results indicate that the relationship between PET receptor distributions and MEG effects warrants further exploration, since elucidating the nature of this relationship may uncover electrophysiologically-derived maps of oscillatory activity as sensitive, time-resolved, and targeted receptor-mapping tools for pharmacological imaging. (C) 2021 The Author(s). Published by Elsevier B.V.

Automated summary

This study investigated the effects of increasing local concentrations of GABA by blocking the reuptake with a GABA transporter 1 (GAT1) blocker, tiagabine. The results showed changes in whole brain activity and functional connectivity across different frequency bands following tiagabine administration, with alterations in frontal and posterior regions. The spatial distribution of these changes overlapped with the distribution of GABA(A) receptors, indicating a link between GABA availability, receptor distribution, and low-frequency network oscillations.