Genetic mouse models of Huntington's and Parkinson's diseases: illuminating but imperfect.
ABSTRACT Genetic mouse models based on identification of genes that cause Huntington's and Parkinson's diseases have revolutionized understanding of the mechanistic pathophysiological progression of these disorders. These models allow the earliest manifestations of the diseases to be identified, and they display behavioral, neuropathological and electrophysiological deficits that can be followed over time in mechanistic and drug studies. An intriguing feature is that they do not reproduce the relatively selective and massive cell loss characterizing the human diseases. There is more information on Huntington's disease models because the disorder involves a single gene that was identified over ten years ago; genetic mutations causing Parkinson's disease are rare and were discovered more recently, and models of the disease have been generated only within the past few years.
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ABSTRACT: Huntington's disease (HD) is a progressive neurological disorder characterised by motor impairments caused by degeneration in the striatum. The mechanism by which the HD mutation leads to the neurodegenerative pathology of HD is still unknown. Recently it was shown that, in HD patients, early pathological changes in white matter precede selective cell death in the striatum. We wondered whether axonal pathology is also an early pathological feature in a transgenic mouse model carrying the HD mutation (R/2 line). R6/2 mice show brain atrophy, a progressive neurological deterioration and skeletal muscle atrophy that resemble those seen in HD patients. However, there is very little neuronal cell loss seen in these animals, even when they show severe symptoms. Here we used sciatic nerve to look for evidence of early neurodegenerative changes in axons of the R6/2 mouse at an ultrastructural level. We observed ultrastructural changes that preferentially affected large myelinated fibres of the sciatic nerve in 10-week-old asymptomatic R6/2 mice. The changes included a significant decrease in the axoplasm diameter of myelinated neurons and an increase in the number of degenerating myelinated fibres compared to age-matched wild type littermates. Myelin thickness and unmyelinated fibre diameter were not affected. The abnormalities described here precede the appearance of overt motor symptoms in the R6/2 mouse and occur in parallel with pathophysiological changes at the neuromuscular junction. We suggest that degenerative changes in axons are likely to contribute to the early pathological phenotype in HD, even in the absence of frank neuronal cell loss.Brain Research 02/2008; 1188:61-8. DOI:10.1016/j.brainres.2007.06.059 · 2.83 Impact Factor
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ABSTRACT: The striatum is critically important in motor, cognitive and emotional functions, as highlighted in neurological disorders such as Huntington's disease (HD) where these functions are compromised. The R6/2 mouse model of HD shows progressive motor and cognitive impairments and alterations in striatal dopamine and glutamate release. To determine whether or not dopamine-dependent neuronal plasticity is also altered in the dorsolateral striatum of R6/2 mice, we compared long term potentiation (LTP) and long term depression (LTD) in striatal slices from R6/2 mice with that seen in slices from wild type (WT) mice. In adult WT mice (aged 8-19 weeks), frequency-dependent bidirectional plasticity was observed. High frequency stimulation (four 0.5 s trains at 100 Hz, inter-train interval 10 s) induced LTP (134+/-5% of baseline), while low frequency stimulation (4 Hz for 15 min) induced LTD (80+/-5% of baseline). LTP and LTD were significantly blocked by the N-methyl-D-aspartic acid (NMDA) receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) (to 93+/-6% and 103+/-8% of baseline respectively), indicating that they are both dependent on NMDA glutamate receptor activation. LTP was significantly blocked by the dopamine D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH-23390) (98+/-8% of baseline), indicating that LTP is dependent on activation of dopamine D(1)-type receptors, whereas LTD was not significantly different (90+/-7%). In adult R6/2 mice (aged 8-19 weeks), LTP was significantly reduced (to 110+/-4% of baseline), while LTD was not significantly different from that seen in WT mice (85+/-6%). These data show that R6/2 mice have impaired dopamine-dependent neuronal plasticity in the striatum. As dopamine-dependent plasticity is a proposed model of striatum-based motor and cognitive functions, this impairment could contribute to deficits seen in R6/2 mice.Neuroscience 07/2007; 146(4):1571-80. DOI:10.1016/j.neuroscience.2007.03.036 · 3.33 Impact Factor
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ABSTRACT: The corticostriatal pathway provides most of the excitatory glutamatergic input into the striatum and it plays an important role in the development of the phenotype of Huntington's disease (HD). This review summarizes results obtained from genetic HD mouse models concerning various alterations in this pathway. Evidence indicates that dysfunctions of striatal circuits and cortical neurons that make up the corticostriatal pathway occur during the development of the HD phenotype, well before there is significant neuronal cell loss. Morphological changes in the striatum are probably primed initially by alterations in the intrinsic functional properties of striatal medium-sized spiny neurons. Some of these alterations, including increased sensitivity of N-methyl-D-aspartate receptors in subpopulations of neurons, might be constitutively present but ultimately require abnormalities in the corticostriatal inputs for the phenotype to be expressed. Dysfunctions of the corticostriatal pathway are complex and there are multiple changes as demonstrated by significant age-related transient and more chronic interactions with the disease state. There also is growing evidence for changes in cortical microcircuits that interact to induce dysfunctions of the corticostriatal pathway. The conclusions of this review emphasize, first, the general role of neuronal circuits in the expression of the HD phenotype and, second, that both cortical and striatal circuits must be included in attempts to establish a framework for more rational therapeutic strategies in HD. Finally, as changes in cortical and striatal circuitry are complex and in some cases biphasic, therapeutic interventions should be regionally specific and take into account the temporal progression of the phenotype.Progress in Neurobiology 05/2007; 81(5-6):253-71. DOI:10.1016/j.pneurobio.2006.11.001 · 10.30 Impact Factor