Complement and glutamate neurotoxicity: Genotypic influences of C5 in a mouse model of hippocampal neurodegeneration

Using mice genetically deficient in the complement (C)-system component C5, this study explored a potential novel role of the C-system in Ca²⁺ - mediated control of glutamate AMPA receptor functions. We found that Ca²⁺ preincubation of frozen brain tissue sections enhances AMPA binding capacity more dynamically in C5 deficient (C5^-) than congenic C5 sufficient (C5⁺) mice. The Ca²⁺ -mediated response was mostly localized to the CA3 and CA1 subdivisions of the pyramidal layers of the hippocampal formation. In C5^- mice, kainic acid (KA) excitotoxicity that models hippocampal neurodegeneration abolished the Ca²⁺ -mediated induction of hippocampal AMPA binding. The changes in AMPA binding preceded temporally and overlapped anatomically the appearance of apoptotic features in the same hippocampal neuron layers. C5^- mice showed greater hippocampal neurodegeneration then C5⁺ mice. NMDA binding controlled for specificity of glutamate-mediated changes and found no C5 genotypic influences. The study gives further credence to the role of the C-system in modifying the intensity and outcome during response to conditions leading to hippocampal neurodegeneration.