The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-typeglutamate-receptor channels (AMPARs) are composed of 4 subunits (GluR1-4); the channels without the GluR2 (GluR-B) subunit are characterized by high Ca2+ permeability. Bergmann glial cells in the cerebellum have Ca(2+)-permeable AMPARs assembled with GluR1 and GluR4. To examine the role of these Ca(2+)-permeable AMPARs, we converted them into Ca(2+)-impermeable receptors by adenoviral-mediated delivery of the GluR2 gene. This resulted in the retraction of the glial processes ensheathing the synapses on Purkinje cell dendritic spines and retard action of the removal of synaptically released glutamate, indicating that glutamate regulates the morphology of glial processes by activating Ca(2+)-permeable AMPARs, and the glial Ca(2+)-permeable AMPARs are indispensable for proper structural and functional interactions between the Bergmann glia and the glutamatergic synapses. Glioblastoma multiforme is the most malignant type of brain tumor. Glioblastoma cells express Ca(2+)-permeable AMPARs assembled from the GluR1 and/or GluR4 subunits, and the conversion of these units to Ca(2+)-impermeable receptors by adenovirus-mediated transfer of the GluR2 gene inhibited cell locomotion and induced apoptosis. In contrast, the overexpression of Ca(2+)-permeable AMPA receptors facilitated migration and proliferation of the tumor cells. Thus, Ca(2+)-permeable AMPA receptors are important in the migration and proliferation of neoplastic glias. The blockage of these receptors may be an attractive therapeutic target for preventing of invasive growth.