Brain gene expression correlates with changes in behavior in the R6/1 mouse model of Huntington’s disease

Abstract

Huntington's disease (HD) is an inherited neurodegeneration that causes a severe progressive illness and early death. Several animal models of the disease have been generated carrying the causative mutation and these have shown that one of the earliest molecular signs of the disease process is a substantial transcriptional deficit. We examined the alterations in brain gene expression in the R6/1 mouse line over the course of the development of phenotypic signs from 18 to 27 weeks. Changes in R6/1 mice were similar to those previously reported in R6/2 mice, and gene ontology analysis shows that pathways related to intracellular and electrical signaling are altered among downregulated genes and lipid biosynthesis and RNA processes among upregulated genes. The R6/1 mice showed deficits in rotarod performance, locomotor activity and exploratory behavior over the time-course. We have correlated the alterations in gene expression with changes in behavior seen in the mice and find that few alterations in gene expression correlate with all behavioral changes but rather that different subsets of the changes are uniquely correlated with one behavior only. This indicates that multiple behavioral tasks assessing different behavioral domains are likely to be necessary in therapeutic trials in mouse models of HD.

Dysregulation of Gene Expression in Primary Neuron Models of Huntington's Disease Shows That Polyglutamine-Related Effects on the Striatal Transcriptome May Not Be Dependent on Brain Circuitry

“…We cannot discriminate between these possibilities at the present time, but nonetheless, we believe that these transcriptomic indicators can serve as robust readouts for the specific molecular and cellular mechanisms that regulate polyQ-dependent effects and responses. This perspective is wellsupported in animal model data, which show that gene expression changes generally correlate well with behavioral measures in animals with early-tomoderate disease signs and that the RNA changes worsen with disease progression (Luthi-Carter et al, 2002;Hodges et al, 2007;Kuhn et al, 2007). Future testing of the effects of individual gene manipulations will eventually allow us to establish the link between transcriptomic changes and particular cellular effects.…”

The Ubiquitous Choline Transporter SLC44A1

“…Three different Huntington disease (HD) models, the brain striata of neonates from YAC transgenic mice [88], PGC-1 alpha knockout mice [89] and Ctip2 knockout mice [90], all express high levels of SCL44A1 mRNA. In addition, in a Tg mice expressing the mutant human Huntington gene, SLC44A1 was upregulated suggesting a role in early HD pathogenesis, likely as part of a cellular defense mechanism against apoptosis [91]. HD is well known for deregulated mitochondrial function and the neuronal SCL44A1 function in mitochondria [52] could be related to the HD apoptosis and impaired energy metabolism [92,93].…”

Dysregulation of dopamine receptor D2 as a sensitive measure for Huntington disease pathology in model mice

“…To develop a quantitative, cell-based preclinical assay system for HD, we have focused on a well-characterized early feature of disease pathology in both these animal models and HD patients, transcriptional dysregulation in the medium spiny neurons (MSNs) of the basal ganglion, a phenotype with substantial consistency among mouse models and between the models and patients (3)(4)(5)(6). One such dysregulated gene, dopamine receptor D2 (DRD2 or D2), shows high expression levels in MSNs of the indirect pathway (striatopalladial) of the basal ganglion, which are among the earliest to die in HD (reviewed in ref.…”