Featured Finding Figure
Accumulating evidence indicates that synchronization of cortical neuronal activity at gamma-band frequencies is important for various types of perceptual and cognitive processes. Experimental models as well as preclinical studies suggest that GABA-A receptor-mediated transmission is required for the induction of network oscillations. However, to date, there is no evidence linking GABA transmission with gamma-band oscillations in humans. Using a novel positron emission tomography (PET) brain-imaging paradigm, we measured the in vivo binding of the benzodiazepine (BDZ) site specific radiotracer [11C]flumazenil at baseline and in the context of elevated GABA levels induced via blockade of the GABA membrane transporter (GAT1) with tiagabine. Preclinical work suggests that increased GABA levels enhance the affinity of GABA-A receptors for BDZ ligands via a conformational change (termed the ‘GABA-shift’). Theoretically, such an increase in affinity of GABA-A receptors should be detected as an increase in the binding of a GABA-A BDZ-receptor site-specific PET radioligand. In fact, we observed significant increases post-GAT1 blockade in [11C]flumazenil binding over baseline values across all cortical brain regions. This is illustrated in Panel A,  showing MRI (top) and coregistered parametric BPND (unitless) maps measured under baseline (middle) and 30 minutes post-tiagabine (bottom) following [11C]flumazenil injection in a healthy female volunteer. Moreover, the ability to increase GABA levels, measured as the change in [11C]flumazenil binding potential, strongly predicted the ability to entrain cortical networks, measured via EEG gamma synchrony in these same subjects (Panel B). These data provide preliminary evidence of the ability to measure acute fluctuations in extracellular GABA levels with PET and provide the first in vivo documentation of the relationship between GABA neurotransmission and gamma-band power in humans.
Frankle et al., "Tiagabine increases [11C]flumazenil binding in cortical brain regions in healthy control subjects: a method for measuring the 'GABA-hift'", Neuropsychopharmacology 34: 624-633, 2009.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
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