Neuroprotective Effects of Synaptic Modulation in Huntington's Disease R6/2 Mice

Abstract

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder in which the neostriatum degenerates early and most severely, with involvement of other brain regions. There is significant evidence that excitotoxicity may play a role in striatal degeneration through altered afferent corticostriatal and nigrostriatal projections that may modulate synaptically released striatal glutamate. Glutamate is a central tenant in provoking excitotoxic cell death in striatal neurons already weakened by the collective molecular events occurring in HD. In addition, transcriptional suppression of trophic factors occurs in human and transgenic mouse models of HD, suggesting that a loss of trophic support might contribute to degeneration. Since anti-glutamate approaches have been effective in improving disease phenotype in HD mice, we examined whether deafferentation of the corticostriatal and nigrostriatal pathways may mitigate striatal stress and neurodegeneration. Both surgical and chemical lesions of the corticostriatal and nigrostriatal pathways, respectively, improved the behavioral, neuropathological, and biochemical phenotype in R6/2 transgenic mice and extended survival. Decortication ameliorated hindlimb clasping, striatal neuron atrophy, and huntingtin-positive aggregates, improved N-acetyl aspartate/creatine levels, reduced oxidative stress, and significantly lowered striatal glutamate levels. In addition, 6-hydroxydopamine lesioned mice showed extended survival along with a significant reduction in striatal glutamate. These results suggest that synaptic stress is likely to contribute to neurodegeneration in HD, whereas transsynaptic trophic influences may not be as salient. Thus, modulation of synaptic influences continues to have therapeutic potential in HD.

In VivoEvidence for NMDA Receptor-Mediated Excitotoxicity in a Murine Genetic Model of Huntington Disease

“…Consistent with these results, the R6/2 transgenic mouse model of HDexpressing exon 1 of the human HD exhibits selectively increased NMDA-evoked current and intracellular calcium (Levine et al, 1999). Recent work shows amelioration of behavioral and neuropathological deficits, and increased survival of R6/2 transgenic mice with decortication, an anti-excitotoxic intervention (Stack et al, 2007). These observations support an important role for NMDAR action, particularly the NR2B subunit, in striatal neuron degeneration in HD.…”

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…At the neuropathological level, decortication reduced the decrease in striatal neuronal area and the number of striatal NIIs, but nigrostriatal deafferentation had no effect on these parameters. Importantly, cortical and substantia nigra lesions resulted in a significant decrease in the striatal levels of either glutamate or glutamate and DA respectively, a change that was accompanied by a reduction in the levels of 8-OH2dG and an increase in the N-acetyl aspartate/creatine ratio, which might reflect an improvement in neuronal survival (Stack et al, 2007a).…”

“…Since altered afferent neuronal projections may modulate the release of glutamate, contributing to striatal excitotoxicity (for review see Gil and Rego, 2008), Stack et al (2007a) examined the effects of deafferentation of the corticostriatal and nigrostriatal pathways in R6/2 mice. Surgical decortication was performed either at 4 or 6 weeks of age through a unilateral cortical aspiration lesion targeting the primary motor cortex, whereas lesion of the nigrostriatal pathway was performed in 6-week-old R6/2 mice through infusion of 6-hydroxydopamine into the substantia nigra.…”

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

“…Perhaps the strongest evidence that these afferents contribute to pathology is the observation that lesions of the cortex [80] or selective removal of mutant huntingtin from cortical pyramidal neurons [81] can improve the behavioral and pathological HD phenotype in HD mouse models. In the context of these observations, it appears that synaptic stress at corticostriatal synapses might be a significant contributor to MSN pathology and might also explain the relationship between cortical and striatal pathology.…”