Observation of synaptic plasticity in the healthy human brain upon Ketamine infusion by 11C-ABP688-PET and 2D J-resolved 1H MRS

Introduction Information processing in the brain relies on the release and diffusion of neurotransmitter molecules across the synaptic cleft and on functional coupling to postsynaptic receptors, which in turn depends on the receptor plasticity. Here, we investigate the functional interplay between the major excitatory neurotransmitter glutamate (Glu) as measured by 1H-MRS and the density of the metabotropic glutamate receptor subtype 5 (mGluR5) assessed by PET. As a tool compound, we used the NMDA-receptor antagonist ketamine that was robustly shown to increase synaptic glutamate release (1). Methods 20 sex- and age-matched healthy subjects completed two imaging sessions (7 days apart) including 11C-ABP688-PET (2) performed on a PET/CT scanner (GE Medical Systems) followed by a 2D J-resolved PRESS 1H-MRS sequence scan (3) on a 3T whole-body MRI scanner (Philips Healthcare). Single voxel spectra were quantified using ProFit V2.0 (3). Metabolite levels were normalized to internal water and a segmentation based volume tissue composition correction was applied (4). PET data were analyzed using PMOD according to well established routines (5); averaged mGluR5 densities from the spectroscopy VOI were extracted. Before PET scanning, either placebo or S-ketamine (i.v. bolus of 0.12 mg/kg, infusion of 0.25 mg/kg/h over 40 min) was administered in a cross-over, double-blind, and randomized study design. Results We found highly significant correlations between post-infusion glutamate levels and mGluR5 densities (r = -.614, p = .005) as well as between post-infusion glutamate and choline levels (r=0.620, p=0.005) in the PACC following ketamine challenge, whereas none of these correlations were apparent under placebo conditions (Fig 2). Additional pairwise comparisons revealed increased total choline (tCho) metabolite levels (p = .044) after ketamine administration (0.440 ± 0.051) compared to placebo (0.418 ± 0.042). Conclusions Pharmacological modulation of the glutamatergic neurotransmitter – receptor system is assessed in the human brain for the first time. The increase in total choline levels along with the glutamate – choline correlation following ketamine infusion are likely to reflect an increase in synaptic glutamate release and related remodeling of cell membranes