Abstract
Mouse models are frequently used to study Huntington’s disease (HD). The onset and severity of neuronal and behavioral pathologies vary greatly between HD mouse models, which results from different huntingtin expression levels and different CAG repeat length. HD pathology appears to depend also on the strain background of mouse models. Thus, behavioral deficits of HD mice are more severe in the FVB than in the C57BL/6 background. Alterations in medium spiny neuron (MSN) morphology and function have been well documented in young YAC128 mice in the FVB background. Here, we tested the relevance of strain background for mutant huntingtin (mHTT) toxicity on the cellular level by investigating HD pathologies in YAC128 mice in the C57BL/6 background (YAC128/BL6). Morphology, spine density, synapse function and membrane properties were not or only subtly altered in MSNs of 12-month-old YAC128/BL6 mice. Despite the mild cellular phenotype, YAC128/BL6 mice showed deficits in motor performance. More pronounced alterations in MSN function were found in the HdhQ150 mouse model in the C57BL/6 background (HdhQ150/BL6). Consistent with the differences in HD pathology, the number of inclusion bodies was considerably lower in YAC128/BL6 mice than HdhQ150/BL6 mice. This study highlights the relevance of strain background for mHTT toxicity in HD mouse models.
Highlights
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder
Analysis of medium spiny neuron (MSN) revealed that YAC128 mice in the C57BL/6 background are only mildly affected
It was previously shown that N-methyl-D-aspartate receptor (NMDAR)-mediated currents increase in MSNs of HD mouse models, which could lead to excitotoxicity
Summary
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. HD patients show symptoms such as motor-dysfunction, starting with involuntary movement and leading to complete loss of intended motion at later disease stages; cognitive deficits; and psychiatric symptoms [1]. The cause of many of these symptoms is the neurodegeneration of the striatum, with apoptosis of GABAergic medium spiny neurons (MSNs) (reviewed in [2]). HD is a trinucleotide repeat disorder and is caused by prolonged CAG repeats (>35) in exon one of the huntingtin gene (HTT). The physiological function of the huntingtin protein (HTT) includes transcriptional regulation, the transport of vesicles, and synaptic activity [5,6]. Mutant HTT (mHTT), disrupts these cellular processes and neuronal functions, leading to neuronal death (for review, see [7])
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