An In Vivo Assay of Synaptic Function Mediating Human Cognition

• Published in: Current biology Vol. 21; no. 15; pp. 1320 - 1325
• Main Authors: Moran, Rosalyn J., Symmonds, Mkael, Stephan, Klaas E., Friston, Karl J., Dolan, Raymond J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 09.08.2011; Cell Press
• Subjects: alpha -Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; alpha -Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; Bayesian analysis; Cognition; cortex; Cortex (prefrontal); Dopamine; Dopamine - physiology; gamma -Aminobutyric acid A receptors; Glutamic acid receptors (ionotropic); Humans; Ion channels; Ion channels (ligand-gated); Magnetoencephalography; Mathematical models; Memory; N-Methyl-D-aspartic acid receptors; physiology; receptors; Short term memory; Signal Transduction; Synapses; Synapses - physiology
• ISSN: 0960-9822; 1879-0445; 1879-0445
• DOI: 10.1016/j.cub.2011.06.053

The contribution of dopamine to working memory has been studied extensively [1–3]. Here, we exploited its well characterized effects [1–3] to validate a novel human in vivo assay of ongoing synaptic [4, 5] processing. We obtained magnetoencephalographic (MEG) measurements from subjects performing a working memory (WM) task during a within-subject, placebo-controlled, pharmacological (dopaminergic) challenge. By applying dynamic causal modeling (DCM), a Bayesian technique for neuronal system identification [6], to MEG signals from prefrontal cortex, we demonstrate that it is possible to infer synaptic signaling by specific ion channels in behaving humans. Dopamine-induced enhancement of WM performance was accompanied by significant changes in MEG signal power, and a DCM assay disclosed related changes in synaptic signaling. By estimating the contribution of ionotropic receptors (AMPA, NMDA, and GABAA) to the observed spectral response, we demonstrate changes in their function commensurate with the synaptic effects of dopamine. The validity of our model is reinforced by a striking quantitative effect on NMDA and AMPA receptor signaling that predicted behavioral improvement over subjects. Our results provide a proof-of-principle demonstration of a novel framework for inferring, noninvasively, neuromodulatory influences on ion channel signaling via specific ionotropic receptors, providing a window on the hidden synaptic events mediating discrete psychological processes in humans. ► We present a DCM capable of assaying neurotransmitter function during human cognition ► We demonstrate this using dopaminergic modulation of working memory and MEG ► We find changes in ionotropic receptors commensurate with dopaminergic enhancement ► We uncover quantitative effects that can predict individual behavioral improvements