Alterations in striatal synaptic transmission are consistent across genetic mouse models of Huntington's disease

Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, U.S.A.
ASN Neuro (Impact Factor: 4.02). 05/2010; 2(3):e00036. DOI: 10.1042/AN20100007
Source: PubMed


Since the identification of the gene responsible for HD (Huntington's disease), many genetic mouse models have been generated. Each employs a unique approach for delivery of the mutated gene and has a different CAG repeat length and background strain. The resultant diversity in the genetic context and phenotypes of these models has led to extensive debate regarding the relevance of each model to the human disorder. Here, we compare and contrast the striatal synaptic phenotypes of two models of HD, namely the YAC128 mouse, which carries the full-length huntingtin gene on a yeast artificial chromosome, and the CAG140 KI (knock-in) mouse, which carries a human/mouse chimaeric gene that is expressed in the context of the mouse genome, with our previously published data obtained from the R6/2 mouse, which is transgenic for exon 1 mutant huntingtin. We show that striatal MSNs (medium-sized spiny neurons) in YAC128 and CAG140 KI mice have similar electrophysiological phenotypes to that of the R6/2 mouse. These include a progressive increase in membrane input resistance, a reduction in membrane capacitance, a lower frequency of spontaneous excitatory postsynaptic currents and a greater frequency of spontaneous inhibitory postsynaptic currents in a subpopulation of striatal neurons. Thus, despite differences in the context of the inserted gene between these three models of HD, the primary electrophysiological changes observed in striatal MSNs are consistent. The outcomes suggest that the changes are due to the expression of mutant huntingtin and such alterations can be extended to the human condition.

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Available from: Carlos Cepeda, Oct 06, 2015
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    • "Nonetheless, we were surprised by the lack of electrophysiological effects at 6 months of age, and our data suggest that the bulk of synaptic deficits in the striatum occur between 6 and 9 months of age. These discrepancies may primarily stem from a different genetic background of multiple models that leads to differences in the number of CAG repeats, or muHTT expression patterns and levels (reviewed in: [9], [10]; see also: [11], [25], [27], [39], [40]). BACHD mice, which the Hu97/18 model is largely based on, have not been fully described using electrophysiological methods [30]. "
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    ABSTRACT: Huntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the gene (HTT) encoding the huntingtin protein (HTT). This mutation leads to multiple cellular and synaptic alterations that are mimicked in many current HD animal models. However, the most commonly used, well-characterized HD models do not accurately reproduce the genetics of human disease. Recently, a new 'humanized' mouse model, termed Hu97/18, has been developed that genetically recapitulates human HD, including two human HTT alleles, no mouse Hdh alleles and heterozygosity of the HD mutation. Previously, behavioral and neuropathological testing in Hu97/18 mice revealed many features of HD, yet no electrophysiological measures were employed to investigate possible synaptic alterations. Here, we describe electrophysiological changes in the striatum and hippocampus of the Hu97/18 mice. At 9 months of age, a stage when cognitive deficits are fully developed and motor dysfunction is also evident, Hu97/18 striatal spiny projection neurons (SPNs) exhibited small changes in membrane properties and lower amplitude and frequency of spontaneous excitatory postsynaptic currents (sEPSCs); however, release probability from presynaptic terminals was unaltered. Strikingly, these mice also exhibited a profound deficiency in long-term potentiation (LTP) at CA3-to-CA1 synapses. In contrast, at 6 months of age we found only subtle alterations in SPN synaptic transmission, while 3-month old animals did not display any electrophysiologically detectable changes in the striatum and CA1 LTP was intact. Together, these data reveal robust, progressive deficits in synaptic function and plasticity in Hu97/18 mice, consistent with previously reported behavioral abnormalities, and suggest an optimal age (9 months) for future electrophysiological assessment in preclinical studies of HD.
    PLoS ONE 04/2014; 9(4):e94562. DOI:10.1371/journal.pone.0094562 · 3.23 Impact Factor
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    • "Whether full-length mutant htt or N-terminal mutant htt plays an important role in synaptic dysfunction remains to be fully investigated and merits discussion here. Many studies have used full-length and N-terminal transgenic mice to identify synaptic dysfunction (Suopanki et al., 2006; Cummings et al., 2010). Because full-length mutant htt is constantly processed via proteolysis to generate N-terminal htt fragments (Zhou et al., 2003; Landles et al., 2010), studies of full-length mutant htt transgenic mice are limited for distinguishing the effects caused by full-length or N-terminal mutant htt. "
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    ABSTRACT: Many genetic mouse models of Huntington's disease (HD) have established that mutant huntingtin (htt) accumulates in various subcellular regions to affect a variety of cellular functions, but whether and how synaptic mutant htt directly mediates HD neuropathology remains to be determined. We generated transgenic mice that selectively express mutant htt in the presynaptic terminals. Although it was not overexpressed, synaptic mutant htt caused age-dependent neurological symptoms and early death in mice as well as defects in synaptic neurotransmitter release. Mass spectrometry analysis of synaptic fractions and immunoprecipitation of synapsin-1 from HD CAG150 knockin mouse brains revealed that mutant htt binds to synapsin-1, a protein whose phosphorylation is critical for neurotransmitter release. We found that polyglutamine-expanded exon1 htt binds to the C-terminal region of synapsin-1 to reduce synapsin-1 phosphorylation. Our findings point to a critical role for synaptic htt in the neurological symptoms of HD, providing a new therapeutic target.
    The Journal of Cell Biology 09/2013; 202(7):1123-1138. DOI:10.1083/jcb.201303146 · 9.83 Impact Factor
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    • "Despite the unexpected dependency of the phenotype to CAG repeat length observed with long repeats, the R6/2 mouse still appears to be a very useful model of HD. Importantly, when strain background and CAG repeat length were controlled for, a knock-in model carrying 150 CAG repeats showed similar pathology and motor changes at 2 yr to those seen in the R6/2 at 12 wk (Woodman et al. 2007); both the YAC128 and a knock-in mouse carrying 140 CAG repeats showed similar alterations in cortical spontaneous synaptic currents, as the R6/2 (Cummings et al. 2010) and the CAG140 and R6/2 mice both show a loss of correlated neuronal activity in the striatum (Miller et al. 2008) and cortex (Walker et al. 2008). It would appear therefore that the R6/2 mouse remains a suitable model in which to study HD and can provide further insight into the effects of highly expanded CAG repeats, which may underlie the similar age of disease onset of juvenile HD patients carrying CAG repeats between 100 and over 250. "
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    ABSTRACT: The R6/2 mouse is the most frequently used model for experimental and preclinical drug trials in Huntington's disease (HD). When the R6/2 mouse was first developed, it carried exon 1 of the huntingtin gene with ~150 cytosine-adenine-guanine (CAG) repeats. The model presented with a rapid and aggressive phenotype that shared many features with the human condition and was particularly similar to juvenile HD. However, instability in the CAG repeat length due to different breeding practices has led to both decreases and increases in average CAG repeat lengths among colonies. Given the inverse relationship in human HD between CAG repeat length and age at onset and to a degree, the direct relationship with severity of disease, we have investigated the effect of altered CAG repeat length. Four lines, carrying ~110, ~160, ~210, and ~310 CAG repeats, were examined using a battery of tests designed to assess the basic R6/2 phenotype. These included electrophysiological properties of striatal medium-sized spiny neurons, motor activity, inclusion formation, and protein expression. The results showed an unpredicted, inverted "U-shaped" relationship between CAG repeat length and phenotype; increasing the CAG repeat length from 110 to 160 exacerbated the R6/2 phenotype, whereas further increases to 210 and 310 CAG repeats greatly ameliorated the phenotype. These findings demonstrate that the expected relationship between CAG repeat length and disease severity observed in humans is lost in the R6/2 mouse model and highlight the importance of CAG repeat-length determination in preclinical drug trials that use this model. Article recommended on Faculty of 1000:
    Journal of Neurophysiology 11/2011; 107(2):677-91. DOI:10.1152/jn.00762.2011 · 2.89 Impact Factor
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