The aging brain refines its circuitry not by random loss but by activity‑scaled synaptic pruning governed by a dynamic C1q/CD47 threshold. Microglia tag weak synapses with C1q "eat me" signals while neighboring neurons display CD47 'don't eat me' cues. In youth, balanced expression preserves useful connections; with age, rising C1q and falling CD47 shift the equilibrium toward excess elimination, contributing to cognitive decline [https://www.bu.edu/kilachandcenter/cognitive-decline-in-old-age-may-be-linked-to-increased-pruning-of-brain-cell-connections/]. However, synaptic fate is not set solely by these basal levels. Neuronal activity modulates the threshold: intermittent, moderate spikes boost astrocytic release of TGF‑β, which locally upregulates CD47 on active synapses, raising their resistance to microglial removal. This creates a feedback loop where use‑dependent activity protects the very circuits that drive it. Conversely, sustained hyperactivity overwhelms homeostatic controls, elevating intracellular calcium that activates complement cascades independent of CD47, forcing elimination of even strongly engaged synapses [https://www.pnas.org/doi/10.1073/pnas.2412391122]. Thus, the same pruning machinery can be protective or pathogenic depending on the pattern and intensity of stimulation.

This hypothesis predicts three testable outcomes in aged mice: (1) Genetic enhancement of astrocytic TGF‑β signaling will increase synaptic CD47 density, lower the C1q/CD47 ratio, and preserve synapse number despite age‑related C1q rise; (2) Pharmacological blockade of TGF‑β receptors will mimic the age‑shift, accelerating synapse loss even when C1q levels are unchanged; (3) Exposing animals to daily bouts of brief, high‑intensity exercise (modeling intermittent acute challenge) will rescue cognitive performance, whereas continuous low‑level stimulation will exacerbate decline. Readouts include immunohistochemistry for C1q and CD47, electrophysiological measures of synaptic strength, and behavioral assays such as the Morris water maze. If manipulating the astrocyte‑neuron CD47 axis alters the susceptibility of synapses to microglial pruning without changing global complement levels, it confirms that activity‑dependent threshold setting, not mere complement accumulation, determines whether the aging brain optimizes or over‑prunes its network.