Deletion of Mea6 in Cerebellar Granule Cells Impairs Synaptic Development and Motor Performance

Abstract

The cerebellum is conceptualized as a processor of complex movements. Many diseases with gene-targeted mutations, including Fahr's disease associated with the loss-of-function mutation of meningioma expressed antigen 6 (Mea6), exhibit cerebellar malformations, and abnormal motor behaviors. We previously reported that the defects in cerebellar development and motor performance of Nestin-Cre;Mea6 ^F/F mice are severer than those of Purkinje cell-targeted pCP2-Cre;Mea6 ^F/F mice, suggesting that Mea6 acts on other types of cerebellar cells. Hence, we investigated the function of Mea6 in cerebellar granule cells. We found that mutant mice with the specific deletion of Mea6 in granule cells displayed abnormal posture, balance, and motor learning, as indicated in footprint, head inclination, balanced beam, and rotarod tests. We further showed that Math1-Cre;Mea6 ^F/F mice exhibited disrupted migration of granule cell progenitors and damaged parallel fiber-Purkinje cell synapses, which may be related to impaired intracellular transport of vesicular glutamate transporter 1 and brain-derived neurotrophic factor. The present findings extend our previous work and may help to better understand the pathogenesis of Fahr's disease.

Keywords: Fahr’s syndrome; Mea6; granule cell; malformation; motor performance; vGluT1.