Molecular and Cellular Mechanisms of Synaptogenesis and Synaptic Refinement During Cerebellar Circuit Formation.

Interactions among molecular recognition systems, neuronal activity, and glial regulation transform early neuronal connectivity into precise functional circuits during brain development. The cerebellum is a powerful model for studying these mechanisms due to its stereotyped and accessible circuitry. Two major excitatory afferent pathways-climbing fibers (CFs), which convey error-related signals to Purkinje cells (PCs), and mossy fibers (MFs), which transmit sensorimotor information via granule cells (GCs) and parallel fibers (PFs)-undergo strengthening, competition, and refinement during postnatal development. Synaptic specificity is established by general and pathway-specific organizers. The neurexin-neuroligin system broadly regulates synapse formation, while the neurexin-CBLN1-GluD2 complex specifies PF-PC synapses and C1qL1-BAI3 signaling stabilizes the dominant CF input during competitive refinement. CF-PC synapse elimination serves as a classic model of activity-dependent competition, where weaker inputs are removed through calcium-dependent mechanisms. In parallel, glial cells regulate synaptic maturation: microglia shape inhibitory environments, and Bergmann glia support glutamate homeostasis, dendritic organization, and synapse stability. PCs integrate CF and PF inputs and provide inhibitory output to the cerebellar nuclei, where convergent excitatory collaterals from CFs and MFs are combined with PC inhibition to generate cerebellar output. Together, these coordinated molecular, cellular, and circuit-level mechanisms establish the synaptic architecture underlying cerebellar computation, motor coordination, and adaptive learning, which are the central focus of this review.