Intracerebroventricular antisense knockdown of Gαi2 results in ciliary stasis and ventricular dilatation in the rat

Abstract

In the CNS, the heterotrimeric G protein Gαi2 is a minor Gα subunit with restricted localization in the ventricular regions including the ependymal cilia. The localization of Gαi2 is conserved in cilia of different tissues, suggesting a particular role in ciliary function. Although studies with Gαi2-knockout mice have provided information on the role of this Gα subunit in peripheral tissues, its role in the CNS is largely unknown. We used intracerebroventricular (icv) antisense administration to clarify the physiological role of Gαi2 in the ventricular system. High resolution MRI studies revealed that continuous icv-infusion of Gαi2-specific antisense oligonucleotide caused unilateral ventricular dilatation that was restricted to the antisense-receiving ventricle. Microscopic analysis demonstrated ependymal cell damage and loss of ependymal cilia. Attenuation of Gαi2 in ependymal cells was confirmed by immunohistochemistry. Ciliary beat frequency measurements on cultured ependymal cells indicated that antisense administration resulted in ciliary stasis. Our results establish that Gαi2 has an essential regulatory role in ciliary function and CSF homeostasis.