ComplementC3-Deficient Mice Fail to Display Age-Related Hippocampal Decline

Abstract

The complement system is part of the innate immune response responsible for removing pathogens and cellular debris, in addition to helping to refine CNS neuronal connections via microglia-mediated pruning of inappropriate synapses during brain development. However, less is known about the role of complement during normal aging. Here, we studied the role of the central complement component, C3, in synaptic health and aging. We examined behavior as well as electrophysiological, synaptic, and neuronal changes in the brains of C3-deficient male mice (C3 KO) compared with age-, strain-, and gender-matched C57BL/6J (wild-type, WT) control mice at postnatal day 30, 4 months, and 16 months of age. We found the following: (1) region-specific and age-dependent synapse loss in aged WT mice that was not observed in C3 KO mice; (2) age-dependent neuron loss in hippocampal CA3 (but not in CA1) that followed synapse loss in aged WT mice, neither of which were observed in aged C3 KO mice; and (3) significantly enhanced LTP and cognition and less anxiety in aged C3 KO mice compared with aged WT mice. Importantly, CA3 synaptic puncta were similar between WT and C3 KO mice at P30. Together, our results suggest a novel and prominent role for complement protein C3 in mediating aged-related and region-specific changes in synaptic function and plasticity in the aging brain.

Complement C3 Expression Is Decreased in Autism Spectrum Disorder Subjects and Contributes to Behavioral Deficits in Rodents

“…Interestingly, higher spine density in pyramidal neurons has been reported in the temporal cortex of ASD patients than in controls [27]. In addition, aged C3 knock out mice performed better on learning and memory tests than aged WT mice [28]. A recent study has found increased C4 mRNA levels in postmortem brain samples from schizophrenia, and reduced synaptic pruning in mice lacking functional C4 [29].…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…The complement cascade, a sequence of protein-protein interactions that “attacks” and damages cell membranes, may also be activated in the aging brain and is implicated in the pathogenesis of AD and ischemic stroke (Arumugam et al, 2009; Stephan et al, 2013; Hong et al, 2016). Genetic or pharmacological inhibition of the complement cascade can ameliorate synapse loss and neuronal death that occurs during normal aging and in mouse models of AD and stroke (Arumugam et al, 2007; Shi et al, 2015; Hong et al, 2016). In addition, activated microglia express an inducible form of NO synthase and produce large amounts of NO that can cause oxidative damage to neurons.…”

Intranasal C3a treatment ameliorates cognitive impairment in a mouse model of neonatal hypoxic–ischemic brain injury

“…Profound region-specific differences in C3-mediated age-dependent elimination of hippocampal CA synapses were recently reported, although the investigators did not address the role of reactive gliosis in this process (Shi et al, 2015). The mechanisms underlying CA region specific effects of C3a on astrocyte activation and the potentially distinct roles of C3b and C3a, the two products of C3 activation, in the hippocampus merit further investigation.…”