Astrocyte-Mediated Synaptic Pruning to Optimize Functional Connectome Efficiency

Astrocytes play a critical role in synaptic pruning and maintenance of neural circuits through complement-mediated elimination of weak or aberrant synaptic connections. This hypothesis proposes that targeted activation of astrocytic complement cascade, specifically through C1q upregulation and subsequent C3 tagging of synapses, can restore optimal functional connectivity patterns in disrupted neural networks. Unlike structural remyelination approaches, this mechanism focuses on refining existing synaptic architecture by selectively eliminating maladaptive connections while preserving or strengthening functionally relevant pathways. Astrocytes would identify synapses for elimination through activity-dependent monitoring of synaptic strength and frequency, using their extensive processes that contact multiple synapses simultaneously. The intervention would involve pharmacological or optogenetic activation of astrocytic complement pathways, particularly targeting the C1q-C3-microglia axis, to enhance pruning efficiency in regions showing aberrant hyperconnectivity or maintaining weak connections that impair network function. This approach shifts from structural white matter repair to functional gray matter optimization, potentially addressing connectome disorders characterized by excessive or inappropriate synaptic connections rather than demyelination. The functional connectome improvements would be measurable through resting-state fMRI, showing increased network efficiency, reduced small-world coefficient disruption, and enhanced modular organization. Evidence would focus on synaptic density changes, complement protein expression levels, microglial activation states, and electrophysiological measures of synaptic strength and network oscillations.