Understanding the cellular neuropathology associated with the motor coordination dysfunction in a mouse model of Williams-Beuren Syndrome

Abstract

Williams-Beuren Syndrome (WBS) is a neurodevelopmental genetic disorder caused by the hemizygous deletion of 28 genes on chromosome 7q11.23. Human gene mapping data suggest that GTF2IRD1 contributes to the neurological characteristics of WBS and Gtf2ird1 knockout (KO) mice display neurological phenotypes that parallel some of the WBS features, including hyperactivity and motor dysfunction. Gtf2ird1 is strongly expressed in the Purkinje neurons (PN) of the cerebellum and the medium spiny neurons (MSNs) of the striatum. Structural changes in these sites could explain the motor abnormalities.

MRI analysis showed no significant difference in overall brain volume. However, calbindin immunofluorescence analysis revealed that both PN density and PN soma size was significantly reduced in KO mice. The Golgi silver impregnation technique revealed a significant reduction in the dendritic branch points and spine density in PNs and a reduction in spine density in MSNs. Primary cell culture of isolated PNs was employed to determine if these defects are cell intrinsic or extrinsic. The total surface area of PN cultured from the cerebellum revealed a reduction in the KO neurons, reflecting a reduction of dendritic arborisation that must be intrinsic.

These studies provide insights into the role of GTF2IRD1 at the cellular level. While no changes were seen in the brains of knockout mice at the macro scale, morphological changes were observed in Gtf2ird1-expressing cell types, suggesting that loss of GTF2IRD1 causes developmental defects in neurons that normally express this protein. Reduction of dendritic tree arborisation, as observed in the KO mice, would reduce the surface area available for synapses with the axon terminals of cerebellar interneurons, therefore impairing the capability of the whole communication network to generate normal output signals, which are transmitted via the axons of the PNs. The reduction in spine density also indicates reduced synaptic activity. PN and MSNs are GABAergic and their inhibitory functions serve to regulate motor movements through axonal projections to the deep cerebellar nuclei and to the globus pallidus and substantia nigra respectively. Hence, these abnormalities in cellular morphology indicate underlying abnormalities in function that could explain the motor dysfunction in Gtf2ird1 KO mice and in WBS.