Mn 2+ dynamics in manganese-enhanced MRI (MEMRI): Ca v 1.2 channel-mediated uptake and preferential accumulation in projection terminals

Neuroimage. 2018 Apr 1;169:374-382. doi: 10.1016/j.neuroimage.2017.12.054. Epub 2017 Dec 19.

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.

Keywords: Activity-dependent; CACNA1C; Calcium channels; Connectomics; Functional imaging; Manganese enhanced MRI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain* / diagnostic imaging
  • Brain* / drug effects
  • Brain* / metabolism
  • Calcium Channels, L-Type / metabolism*
  • Chlorides / administration & dosage*
  • Image Enhancement / methods*
  • Magnetic Resonance Imaging / methods*
  • Male
  • Manganese / metabolism*
  • Manganese Compounds / administration & dosage*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism*
  • Thalamus / diagnostic imaging
  • Thalamus / drug effects
  • Thalamus / metabolism

Substances

  • CACNA1C protein, mouse
  • Calcium Channels, L-Type
  • Chlorides
  • Manganese Compounds
  • Manganese
  • manganese chloride