Correction of cerebellar movement related deficits by normalizing Dyrk1a copy number in the Ts65Dn mouse model for Down syndrome

Abstract

Elucidation of the underlying mechanisms involved in brain related deficits of Down syndrome (DS) would be useful for consideration of therapeutic interventions. Several DSspecific phenotypes have been hypothesized to be linked to altered expression or function of specific trisomic genes. One such gene of interest is D YRK1A , which has been implicated in behavioral functions of the hippocampus and cerebellum. The Ts65Dn mouse model for DS includes a triplication of D yrk1a in addition to a triplication of >100 other human chromosome 21 mouse orthologs. To evaluate the role of D yrk1a in cerebellar function, we have genetically normalized the D yrk1a copy number in otherwise trisomicTs65Dn mice and reduced D yrk1a copy number in otherwise euploid mice (2N) for a total of 3 alternative genetic doses of D yrk1a: EuploidDyrk1a +/+ , EuploidDyrk1a +/, Ts65DnDyrk1a +/+/+ , and Ts65DnDyrk1a +/+/. Cerebellar movementrelated function in these knockdown models is being assessed through a novel behavioral balance beam task. Additionally, levels of D yrk1a activity in the cerebellum for all genotypes were analyzed by HPLC. We have previously demonstrated that Ts65DnDyrk1a +/+/+ mice perform worse in the balance beam task in comparison to EuploidDyrk1a +/+ mice. Preliminary results of the current study do not indicate such a difference among Ts65DnDyrk1a +/+/+ mice in comparison to EuploidDyrk1a +/+ mice. We hypothesize that the lack of replication of the previous findings may be due to differences in postweaning housing environments. Mice in the previous study were singlehoused, whereas mice in the present study were grouphoused, which may help mitigate motor deficits in the trisomic mice. Additionally, current trends display a deficit in balance beam performance of both the EuploidDyrk1a +/and the Ts65DnDyrk1a +/+/groups, which suggests that reducing the copy number of D yrk1a by one may have detrimental effects on motor coordination. Concomitant analysis of the balance beam performances and Dyrk1a activity levels may indicate the sensitivity of the balance beam task to assess the role Dyrk1a activity in cerebellar function.