Impact of manganese on primary hippocampal neurons from rodents

Hippocampus. 2014 May;24(5):598-610. doi: 10.1002/hipo.22252. Epub 2014 Mar 3.

Abstract

Manganese-enhanced magnetic resonance imaging (MEMRI) is a powerful tool for in vivo tract tracing or functional imaging of the central nervous system. However Mn(2+) may be toxic at high levels. In this study, we addressed the impact of Mn(2+) on mouse hippocampal neurons (HN) and neuron-like N2a cells in culture, using several approaches. Both HN and N2a cells not exposed to exogenous MnCl2 were shown by synchrotron X-ray fluorescence to contain 5 mg/g Mn. Concentrations of Mn(2+) leading to 50% lethality (LC50) after 24 h of incubation were much higher for N2a cells (863 mM) than for HN (90 mM). The distribution of Mn(2+) in both cell types exposed to Mn(2+) concentrations below LC50 was perinuclear whereas that in cells exposed to concentrations above LC50 was more diffuse, suggesting an overloading of cell storage/detoxification capacity. In addition, Mn(2+) had a cell-type and dose-dependent impact on the total amount of intracellular P, Ca, Fe and Zn measured by synchrotron X-ray fluorescence. For HN neurons, immunofluorescence studies revealed that concentrations of Mn(2+) below LC50 shortened neuritic length and decreased mitochondria velocity after 24 h of incubation. Similar concentrations of Mn(2+) also facilitated the opening of the mitochondrial permeability transition pore in isolated mitochondria from rat brains. The sensitivity of primary HN to Mn(2+) demonstrated here supports their use as a relevant model to study Mn(2+) -induced neurotoxicity.

Keywords: MEMRI; X-ray synchrotron; hippocampal neurons; manganese; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Hippocampus / cytology*
  • Manganese / pharmacology*
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Neuroblastoma / pathology
  • Neurons / drug effects*
  • Neurons / ultrastructure
  • Phosphorus / metabolism
  • Spectrometry, X-Ray Emission
  • Time Factors
  • Trace Elements / pharmacology*
  • Zinc / metabolism

Substances

  • Trace Elements
  • Phosphorus
  • Manganese
  • Zinc
  • Calcium