Kainic Acid-Induced Neuronal Degeneration in Hippocampal Pyramidal Neurons Is Driven by Both Intrinsic and Extrinsic Factors: Analysis of FVB/N↔C57BL/6 Chimeras

Abstract

The excitotoxic effects of kainic acid (KA) in the mouse hippocampus is strain dependent. Following KA administration, the large majority of hippocampal pyramidal cells die in the FVB/N (FVB) mouse, while the pyramidal cells of the C57BL/6 (B6) strain are largely spared. We generated aggregation chimeras between the sensitive FVB and the resistant B6 strains to investigate whether intrinsic or extrinsic features of a neuron confer cell vulnerability or resistance to KA. The constitutive expression of transgenic green fluorescence protein (GFP) or β-galactosidase expressed from the ROSA26 locus was used to mark cells in FVB or B6 mice, respectively. These makers enable the identification of cells from each parental genotype while TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated dUTP nick end labeling)-staining labeled dying cells. The analysis of the percentage of dying cells in FVB-GFP ↔ B6-ROSA chimeras yielded an intriguing mix of both intrinsic and extrinsic factors in the readout of cell phenotype. Thus, normally resistant B6-ROSA pyramidal neurons demonstrated an increasing sensitivity to KA, in a linear fashion, when the percentage of FVB-GFP cells was increased, either across chimeras or in different regions of the same chimera. However, the death of B6-ROSA pyramidal cells never exceeded ∼70% of the total amount of B6 neurons regardless of the amount of FVB cells in the chimeric hippocampus. In a similar manner, FVB-GFP cells show lower amounts of cell death in chimeras that are colonized by B6-ROSA cells, but again, are never fully rescued. These data indicate that both intrinsic and extrinsic factors modulate the sensitivity of hippocampal pyramidal cells to kainic acid.