Concentration-dependent bidirectional modification of evoked synaptic transmission by gadolinium and adverse effects of gadolinium-based contrast agent

Abstract

Gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) are gadolinium chelates and can leave gadolinium in brain regions after administration, causing damage to brain tissues. However, the exact effects of gadolinium on synaptic function and the underlying mechanisms have not yet been elucidated. Here, we report that gadolinium differentially modulates evoked and spontaneous synaptic transmission and induces bidirectional changes in the efficacy of evoked synaptic transmission in the mouse hippocampus in a concentration-dependent manner. Low concentration gadolinium (100 μM) modestly potentiated evoked field excitatory postsynaptic potentials (fEPSPs), while high concentration gadolinium induced group 1 metabotropic glutamate receptor (mGluR)-, endocannabinoid (eCB)-, and purinergic P2Y1 receptor (P2Y1R)-dependent, presynaptically-expressed long-term depression (LTD). Higher concentration of gadolinium (1,000 μM) also induced NMDAR- and mGluR-independent, partially P2Y13R-dependent, postssynaptically-expressed LTD. Low concentration gadolinium greatly increased miniature excitatory postsynaptic current (mEPSC) frequency, while high concentration gadolinium much more robustly increased its frequency and amplitude. Finally, we found that evoked EPSCs were not affected by a macrocyclic GBCA, gadoterate meglumine (Gd-GOTA, Magnescope). However, evoked EPSCs were enhanced by a linear GBCA, gadopentetate dimeglumine (Gd-DTPA, Magnevist), at 100 μM, a clinically relevant concentration in the human brain after repeated clinical GBCA administration and in the cerebrospinal fluid in the rodent brain during experimental GBCA administration. Thus, evoked and spontaneous synaptic transmission are independently modulated by gadolinium. Furthermore, Gd-GOTA effectively chelated gadolinium; however, Gd-DTPA had side effects on the evoked synaptic transmission, presumably because it did not completely chelate gadolinium.Significance Statement Gadolinium is used in gadolinium-based contrast agents (GBCAs), gadolinium chelates, for magnetic resonance imaging examination. Herein, we report influences of gadolinium and GBCAs on synaptic transmission. High concentration gadolinium (500-1000 μM) induces metabotropic glutamate receptor-, endocannabinoid-, and purinergic receptor-dependent long-term depression, and simultaneously enhances spontaneous glutamate release. In contrast, gadolinium enhances evoked synaptic transmission at 100 μM, which is the concentration observed in the human patient brain after repeated GBCA administration. Gadoterate meglumine (Magnescope, 100 μM), a macrocyclic GBCA, did not affect synaptic transmission. However, gadopentetate dimeglumine (Magnevist, 100 μM), a liner GBCA, enhanced synaptic transmission, suggesting that gadopentetate dimeglumine does not fully chelate gadolinium, which can have a negative effect on brain function.