LAUSR

ABSTRACT Manganese‐enhanced magnetic resonance imaging (MEMRI) exploits the biophysical similarity of Ca2+ and Mn2+ to map the brain's activity in vivo. However, to what extent different Ca2+ channels contribute to the enhanced signal that MEMRI provides and how Mn2+ dynamics influence Mn2+ brain accumulation after systemic administration of MnCl2 are not yet fully understood. Here, we demonstrate that mice lacking the L‐type Ca2+ channel 1.2 (Cav1.2) in the CNS show approximately 50% less increase in MEMRI contrast after repeated systemic MnCl2 injections, as compared to control mice. In contrast, genetic deletion of L‐type Ca2+ channel 1.3 (Cav1.3) did not reduce signal. Brain structure‐ or cell type‐specific deletion of Cav1.2 in combination with voxel‐wise MEMRI analysis revealed a preferential accumulation of Mn2+ in projection terminals, which was confirmed by local MnCl2 administration to defined brain areas. Taken together, we provide unequivocal evidence that Cav1.2 represents an important channel for neuronal Mn2+ influx after systemic injections. We also show that after neuronal uptake, Mn2+ preferentially accumulates in projection terminals. Graphical abstract Figure. No Caption available. HighlightsCav1.2 is an important entrance point for Mn2+ into neurons.Mn2+ entering neurons via Cav1.2 preferentially accumulates in projection terminals.This suggests MEMRI as a tool for the identification of activated neuronal circuits.