Reduced hippocampal neurogenesis in R6/2 transgenic Huntington's disease mice

Abstract

We investigated whether cell proliferation and neurogenesis are altered in R6/2 transgenic Huntington's disease mice. Using bromodeoxyuridine (BrdU), we found a progressive decrease in the number of proliferating cells in the dentate gyrus of R6/2 mice. This reduction was detected in pre-symptomatic mice, and by 11.5 weeks, R6/2 mice had 66% fewer newly born cells in the hippocampus. The results were confirmed by immunohistochemistry for the cell cycle markers Ki-67 and proliferating cell nuclear antigen (PCNA). We did not observe changes in cell proliferation in the R6/2 subventricular zone, indicating that the decrease in cell proliferation is specific for the hippocampus. This decrease corresponded to a reduction in actual hippocampal neurogenesis as assessed by double immunostaining for BrdU and the neuronal marker neuronal nuclei (NeuN) and by immunohistochemistry for the neuroblast marker doublecortin. Reduced hippocampal neurogenesis may be a novel neuropathological feature in R6/2 mice that could be assessed when evaluating potential therapies.

Adult Neurogenesis in Neurodegenerative Diseases: Figure 1.

“…Several studies have reported reduced progenitor proliferation rates in the DG in both mouse models (the slower progressing R6/1 line) (Lazic et al 2004(Lazic et al , 2006 and R6/2 mice with a fast disease progression (Gil et al 2004(Gil et al , 2005Phillips et al 2005;Kohl et al 2007). This resulted in a reduction of newly generated neurons, although, in most reports, neuronal differentiation was not compromised.…”

The antidepressant sertraline improves the phenotype, promotes neurogenesis and increases BDNF levels in the R6/2 Huntington's disease mouse model

“…There are contrasting reports in neurogenesis between HD human brains and mouse models (Phillips et al, 2006;Phillips et al, 2005;Grote et al, 2005;Gil et al, 2005;Tattersfield et al, 2005;Lazic et al, 2004;Curtis et al, 2003). For example, reduced neurogenesis has been reported in R6/2 mice (Phillips et al, 2006;Phillips et al, 2005;Gil et al, 2005), but in humans, there was increased proliferation and neurogenesis (Curtis et al, 2003).…”

“…These studies suggest that increasing BDNF levels is beneficial in HD. Altered neurogenesis has been reported in HD mouse models and in human postmortem brains (Phillips et al, 2006;Phillips et al, 2005;Grote et al, 2005;Gil et al, 2005;Lazic et al, 2004;Curtis et al, 2003). In addition to promoting neuronal survival, BDNF also regulates neurogenesis (Duman, 2004;Cotman and Berchtold 2002).…”

Cell therapy in Huntington disease

“…11,80,119,150 The microenvironment plays a key role in maintaining the neurogenic potential of the adult brain; 19,117,136 it also plays a role in the fate restriction of endogenous NSCs in neurogenic regions. 95,137,145 Abnormalities in adult neurogenesis as exhibited in both HD transgenic mice 63,64,89,90,124,146 and humans 35-37 may have clinical relevance for patients afflicted with HD. Although striatal pathophysiology contributes to some motor and cognitive defects in patients with HD, 5 nonstriatal pathology, especially of the hippocampus, may mediate aspects of affective and cognitive deficits in HD.…”

“…Although striatal pathophysiology contributes to some motor and cognitive defects in patients with HD, 5 nonstriatal pathology, especially of the hippocampus, may mediate aspects of affective and cognitive deficits in HD. 35,121,131 Neural progenitor cell proliferation, survival, and structure are abnormal in the DG of mice transgenic for the human HD gene, 63,64,89,90,124 an effect that can be partially restored by environmental enrichment. 90 Environmental enrichment or physical activity, which modulates the proliferation and survival of newly formed neurons, improves motor and cognitive deficits in HD transgenic mice models.…”