Fig. 8.

Summary of age-related alterations in complement cascade C1q signaling in dlPFC layer III and hypotheses relating to neuronal pathology. Age-related increases in C1q expression accumulate in the glia and postsynaptically in dendritic spines and dendritic shafts, with a sparser expression in axon terminals. Within dendritic spines, C1q aggregates in perisynaptic and extrasynaptic subcompartments in association with the spine apparatus and within the PSD of glutamatergic synapses. Within dendritic shafts, C1q aggregates in close proximity to dysmorphic mitochondria. We hypothesize that the rise in complement C1q signaling in the aged dlPFC may be due to the age-related dysregulation of feedforward cAMP-PKA-calcium signaling, which increases the open state of nearby K⁺ channels, but may also cause calcium overload of the mitochondria and the initiation of inflammatory actions. The intra-neuronal localization of C1q might signal to microglia and astrocytes, via a mechanism that remains to be delineated, to eliminate dysfunctional neuronal elements and synapses by phagocytosis