Abstract
Huntington’s Disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by deleterious expansion of CAG repeats in the Huntingtin gene and production of neurotoxic mutant Huntingtin protein (mHTT). The key pathological feature of HD is a profound degeneration of the striatum and a loss of cortical volume. The initial loss of indirect pathway (D2) medium spiny neuron (MSN) projections in early stages of HD, followed by a loss of direct pathway (D1) projections in advanced stages has important implications for the trajectory of motor and cognitive dysfunction in HD, but is not yet understood. Mouse models of HD have yielded important information on the effects and mechanisms of mHTT toxicity; however, whether these models recapitulate differential vulnerability of D1 vs. D2 MSNs is unknown. Here, we employed 12-month-old Q175+/- x D2-eGFP mice to examine the detailed structural and functional properties of D1 vs. D2 MSNs. While both D1 and D2 MSNs exhibited increased input resistance, depolarized resting membrane potentials and action potential threshold, only D1 MSNs showed reduced rheobase, action potential amplitude and frequency of spontaneous excitatory postsynaptic currents. Furthermore, D1 but not D2 MSNs showed marked proliferative changes to their dendritic arbors and reductions in spine density. Immunohistochemical assessment showed no loss of glutamatergic afferent inputs from cortical and subcortical sources onto identified D1 and D2 MSNs. Computational models constrained by empirical data predict that the increased dendritic complexity in Q175+/- D1 MSNs likely leads to greater dendritic filtering and attenuation of signals propagating to the soma from the dendrites. Together these findings reveal that, by twelve months, D1 and D2 MSNs exhibit distinctive responses to the presence of mHTT in this important mouse model of HD. This further highlights the need to incorporate findings from D1 and D2 MSNs independently in the context of HD models.
Highlights
Huntington’s Disease (HD) is a progressive neurodegenerative disorder affecting cognitive, psychiatric, and motor functions [1,2]
These data replicate those in previous reports of physiological changes to unidentified medium spiny neuron (MSN) in Q175+/- compared to WT mice [27,28]
As previously reported [54,55] both rheobase and action potential threshold were significantly higher in D1 than in D2 MSNs, Rn and Vr did not differ between the subtypes
Summary
Huntington’s Disease (HD) is a progressive neurodegenerative disorder affecting cognitive, psychiatric, and motor functions [1,2]. Longitudinal PET imaging in HD gene carriers reveals a greater initial loss of D2 compared to D1 receptor binding in the striatum [22,23]. These sequential changes in indirect and direct pathway projections to target structures are widely believed to contribute to the biphasic trajectory of motor dysfunction in HD, in which initial disruption of the indirect pathway results in uncontrolled choreiform movements while later in the disease the additional loss of the direct pathway leads to bradykinesia
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