Abstract
Huntington disease (HD) is an inherited neurodegenerative disease characterized by a clinical triad of motor, psychiatric and cognitive symptoms. HD is caused by a CAG repeat expansion in the gene encoding the huntingtin protein. Homozygosity for the HD-causing mutation is extremely rare; thus, the majority of HD patients express the mutant huntingtin protein in addition to reduced levels of the non-pathogenic huntingtin protein. Deficits in synaptic plasticity, including hippocampal long-term potentiation (LTP), have been identified in various mouse models of HD and are thought to contribute to the debilitating cognitive symptoms associated with the disease. However, the bulk of these studies used N-terminal fragment or homozygous knock-in mouse models of HD at symptomatic ages, and our understanding of the onset and progression of synaptic plasticity deficits in the HD brain is lacking. To better understand the time-course of synaptic plasticity deficits in HD, as well as the impact of heterozygous and homozygous huntingtin mutations, we quantified basal synaptic connectivity, presynaptic release probability, presynaptically mediated post-tetanic potentiation (PTP) and postsynaptically mediated LTP at presymptomatic, early symptomatic and late symptomatic ages in heterozygous and homozygous Q175FDN knock-in HD mice. Our results demonstrate clear age-dependent effects of the HD-causing mutation on both short and long-term plasticity that generally emerge earlier in homozygous mice. Interestingly, deficits in presynaptic short-term plasticity were more closely linked to disease progression than deficits in postsynaptic LTP, and heterozygous mice were more susceptible to an LTP deficit when induced by high frequency stimulation compared to theta burst stimulation. To the best of our knowledge, the present study represents the most thorough characterization to date of the onset and progression of hippocampal synaptic plasticity deficits in a mouse model of HD, and should prove valuable to future studies exploring cellular mechanisms underlying the debilitating cognitive decline in HD.
Highlights
Huntington disease (HD) is a fatal autosomal dominant neurodegenerative disease that affects approximately 1–2 individuals per 10,000 (Fisher and Hayden, 2014)
The current study demonstrates clear increases in basal synaptic strength as well as deficits in short- and longterm synaptic plasticity in the hippocampus of Q175FDN mice
Our data suggest that the various plasticity deficits in the HD hippocampus are unlikely to be mediated by a common mechanism; rather, independently developing perturbations in a variety of signaling pathways are likely to combine to contribute to HD hippocampal pathogenesis
Summary
Huntington disease (HD) is a fatal autosomal dominant neurodegenerative disease that affects approximately 1–2 individuals per 10,000 (Fisher and Hayden, 2014). Plasticity Deficits in Huntington Disease expression levels of non-expanded (i.e., non-pathogenic) huntingtin (Cattaneo et al, 2005; Dietrich et al, 2017), results in the progressive deterioration of much of the neuroaxis, with devastating effects observed in the striatum. The monogenic nature of HD has resulted in the identification of presymptomatic gene carriers (pre-HD); from this pre-HD population, it was discovered that subtle impairments in cognitive function are often evident as many as 15 years prior to a formal diagnosis based on unequivocal motor signs (Paulsen et al, 2008). In a population of pre-HD individuals predicted to be at least 14 years away from a formal diagnosis of HD, approximately 40% reached the criteria for mild cognitive impairment, with higher rates observed in those closer to a motor diagnosis (Duff et al, 2010). Of particular interest to the present study is HD-associated pathophysiology in the hippocampus, a brain region critically involved in cognitive function
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