Impaired dopamine release and uptake in R6/1 Huntington's disease model mice

Abstract

Huntington’s disease (HD) is a progressive, neurodegenerative movement disorder. Here, we used fast-scan cyclic voltammetry to measure dopamine release and uptake in striatal brain slices from R6/1 HD model mice. Peak dopamine release ([DA]max) was significantly diminished in R6/1 mice (52% of wild-type at 24 weeks of age). Similarly, dopamine released per locally applied electrical stimulus pulse ([DA]p), which is [DA]max corrected for uptake and electrode performance, was also diminished in R6/1 mice (43% of wild-type by 24 weeks of age). Moreover, Vmax, the maximum rate of dopamine uptake, obtained by modeling the stimulated release plots, was decreased at 16 and 24 weeks of age in R6/1 mice (51 and 48% of wild-type, respectively). Thus, impairments in both dopamine release and uptake appear to progress in an age-dependent manner in R6/1 mice.

Dysfunctional Dopaminergic Neurones in Mouse Models of Huntington's Disease: A Role for SK3 Channels

“…In sharp contrast, dopamine release was found to be severely reduced in striatal slices from R6/1 mice and is in accordance with previous investigations showing that dopamine release is also reduced [26,61]. The aetiology of this failure in dopamine release is likely to be more complex.…”

“…Studies using these genetic models have also added to the controversy, with some laboratories reporting dramatic reductions in striatal dopamine levels [24,25,26,27] or loss of dopamine signalling [28,29] and others suggesting that dopamine levels may be elevated [30] or toxic [31,32]. …”

Early Dysfunction of Neural Transmission and Cognitive Processing in Huntington’s Disease

“…Whenever a neurotransmitter system is dampened, it produces functional loss, either within the same system (movement-related), or within an alternate system that also depends on that neurotransmitter (cognitive or strategic). Evidence from animal models indicates that the capacity to release DA is substantially reduced in the context of both huntingtin mutations (Ortiz et al, 2010(Ortiz et al, , 2011Tang et al, 2007;Johnson et al, 2006Johnson et al, , 2007Yohrling et al, 2003), and the mitochondria-compromising neurotoxin, 3-nitroproprionic acid (3-NP), also used to model HD (Kraft et al, 2009). These 3-NP findings suggest that compromised DA may arise in part from a cellular energy deficit.…”

“…Yohrling and colleagues (2003) also looked at loss of tyrosine hydroxylase, the rate limiting enzyme in DA production, in the substantia nigra of postmortem HD brains and found over 30% loss, which would functionally compromise DA availability. Therefore, ironically, despite the implications of DA overactivity that may arise from the clinical effectiveness of dampening this neurotransmitter with currently FDAapproved drugs such as tetrabenazine (Guay, 2010;de Tommaso et al, 2011), animal research indicates DA function is, in fact reduced, even prior to motor symptom expression (Ortiz et al, 2010(Ortiz et al, , 2011Johnson et al, 2006;Bibb et al, 2000).…”

“…Perhaps for this reason, unmedicated Parkinson's patients who are tested early in their disease progression (as DA diminishes well before movement deficits emerge in PD) exhibit impairment in "set-shifting" tasks that require cognitive flexibility (Owen et al, 1992). The previously described declines in presymptomatic DA release capacity exposed in HD animal models (Ortiz et al, 2010(Ortiz et al, , 2011 would predict a DA-related deficit in behavioral flexibility in HD patients. Such deficits were found by Lawrence and his colleagues (1998b), who showed that pre-HD mutation carriers were impaired on cognitive tests in a manner that correlated with DA receptor binding levels measured by PET scans.…”