Microglia act as active sculptors of neural circuits by sensing activity patterns, removing weak synapses and modulating synaptic strength, a role that connects cellular immune functions to learning, development and disease. Beth Stevens from Boston Children’s Hospital and Harvard Medical School provided evidence that classical complement proteins label less active synapses for elimination, recruiting microglia to phagocytose those connections and shaping circuit refinement during development. Marie-Eve Tremblay at Université Laval used in vivo imaging to show that microglial processes make transient contacts with dendritic spines in sensory cortex and that those contacts change with sensory experience, linking local behavior and environment to synaptic remodeling.
Complement-mediated pruning
Complement proteins such as C1q and C3 are expressed in neurons and accumulate at specific synapses, where recognition by microglial complement receptors leads to engulfment and removal. This mechanism explains how relative synaptic activity can result in selective elimination: less active inputs accumulate complement tags and are preferentially removed, while active synapses are preserved. The spatial specificity of this process contributes to regional differences in pruning, for example between sensory cortices and hippocampus, and helps account for critical-period plasticity observed across cultures of development and learning.
Neurotrophic signaling and cytokines
Microglia also release soluble factors that influence synaptic function. Christopher N. Parkhurst at the Massachusetts Institute of Technology demonstrated that microglial brain-derived neurotrophic factor supports learning-dependent spine formation, indicating a constructive role beyond removal. Cytokines such as tumor necrosis factor alpha and interleukin 1 modulate synaptic scaling and long-term potentiation, a theme synthesized in reviews by Helmut Kettenmann at the Max Delbrück Center for Molecular Medicine. Through both contact-mediated interactions and secreted signals, microglia adjust synaptic strength to match network demands.
Consequences for health and society emerge from these cellular actions: altered microglial pruning and signaling are implicated by multiple research groups in developmental disorders and in neurodegenerative conditions where excessive synapse loss impairs cognition. Because microglial activity is sensitive to systemic environment, infections, stress and aging, cultural and territorial differences in exposure and healthcare can influence population-level outcomes. Understanding microglial control of synaptic plasticity clarifies a fundamental link between immune biology and brain function and points to targeted strategies that may restore healthy connectivity without broadly suppressing immune defenses.
