As one of the central features of the innate immune system, the complement cascade assists in removing pathogens from the body. Additionally, the complement system acts in brain development to refine synaptic connections by removing those that are weak or misdirected. The role of the complement cascade, specifically of the central component C3, in synaptic degradation in the aging brain, however, remains unclear. Although synaptic pruning is key to healthy early brain development, synaptic degradation in the adult brain may be a precursor of aging and neurodegenerative disease that results in neuronal loss. Recently, a research team led by Dr. Cynthia A. Lemere of the Ann Romney Center for Neurologic Diseases at Brigham and Women's Hospital utilized C3-deficient mice, B6;129S4-C3tm1Crr/J (003641) to investigate whether the C3-mediated synaptic pruning mechanisms at work in the developing brain also contribute to cognitive decline in the aging brain.
Consistent with earlier reports, Lemere's team observed synaptic reductions in the CA3 layer and in the dentate gyrus in the hippocampus of adult C57BL/6J (000664) wild-type (WT) mice. Interestingly, they did not observe such changes in the CA1 layer, suggesting that synaptic loss in the aging brain is region-specific. Further, the researchers found that C3 protein levels were elevated in WT hippocampus during early postnatal development (P2), declined sharply by P30, and rebounded modestly but significantly at 16 months. The rise in C3 protein level correlated with decreases in synaptic puncta and synaptophysin densities and synaptic protein, neuron loss, and reduced synaptic plasticity. These changes were not observed in C3-deficient mice, suggesting that C3 is required for these developmental changes.
Research on cognitive decline and age-related behavioral deficits primarily focuses on morphological and electrophysiological changes in the hippocampus and many studies report age-related deficits in learning and memory due reduced hippocampal synaptic connections and neuron density. To translate the changes they observed in their mice to a behavioral phenotype, Lemere's group thoroughly examined hippocampal-dependent learning and memory in both WT and C3-deficient mice, and their responses to anxiety. In the water T-maze test, which measures spatial learning during acquisition and cognitive flexibility during recall, 16 month-old C3-deficient mice performed significantly better compared to WT controls. Aged C3-deficient mice also performed significantly better than WT mice in the contextual fear conditioning task, which evaluates memory associated with aversive stimuli, and C3-deficient mice display reduced anxiolytic behavior, evaluated via the elevated plus maze and open-field assessment. Based on these results Lemere’s team concluded that complement C3, or associated downstream signaling, play an important role in age-related cognitive decline and behavioral deficits.