Neuronal DSCAM regulates the peri-synaptic localization of GLAST in Bergmann Glia for the functional synapse formation

Abstract Synapse formation and functioning are vital for neural network development. Astrocytes ensheathing synapses enable appropriate synapse functioning through glutamate clearance from the synaptic cleft; however, it remains unclear how astrocytic glutamate transporter proteins function at peri-synaptic contact. Here, we report that down syndrome cell adhesion molecule (DSCAM) in Purkinje cells controls climbing fiber (CF) synaptogenesis in the developing cerebellum. Dscam-mutant mice mimicked loss-of-function mutations in the astrocytic glutamate transporter GLAST expressed in Bergmann glia. These mice showed impaired glutamate clearance by the delocalization of GLAST, which complexed with the extracellular domain of DSCAM. Riluzole-induced reduction of free glutamate at the synaptic cleft rescued the impairment of CF synapse formation in Purkinje cell-selective Dscam-deficient mice. DSCAM was required for motor learning, but not gross motor coordination. In conclusion, the intercellular association of synaptic and astrocyte proteins in the tripartite synapse is critical for synapse formation and functioning in neural transmission.