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.
Highlights
Huntington disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the gene (HTT) encoding the huntingtin protein [1]
A recent and promising approach to the treatment of HD utilizes antisense oligonucleotide (ASO) technology to knock down expression levels of mutated huntingtin protein (muHTT)
Cell firing characteristics were assessed in current clamp by recording membrane voltage changes in response to injected current steps (50pA increments starting from -200pA, 1 s each; Fig. 1D)
Summary
Huntington disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the gene (HTT) encoding the huntingtin protein [1]. Expansion of the CAG beyond 36 repeats produces a mutated huntingtin protein (muHTT) with an expanded polyglutamine (polyQ) tract in its N-terminal region. Expression of muHTT results in profound disruption of a wide variety of cellular processes (reviewed in: [2]), including synaptic transmission and plasticity (reviewed in: [3,4,5]). ASO administration has been employed to effectively silence the expression of a variety of genes of interest and relies on a specific design and efficient delivery of short, synthetic, modified nucleic acids. A number of preclinical and clinical studies, targeting different neurological and nonneurological disorders, have demonstrated ASO efficiency with no severe adverse effects (reviewed in: [6,7])
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