Reduction in Subventricular Zone-Derived Olfactory Bulb Neurogenesis in a Rat Model of Huntington’s Disease Is Accompanied by Striatal Invasion of Neuroblasts

Abstract

Huntington’s disease (HD) is an inherited progressive neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the huntingtin gene (HTT). The primary neuropathology of HD has been attributed to the preferential degeneration of medium spiny neurons (MSN) in the striatum. Reports on striatal neurogenesis have been a subject of debate; nevertheless, it should be considered as an endogenous attempt to repair the brain. The subventricular zone (SVZ) might offer a close-by region to supply the degenerated striatum with new cells. Previously, we have demonstrated that R6/2 mice, a widely used preclinical model representing an early onset HD, showed reduced olfactory bulb (OB) neurogenesis but induced striatal migration of neuroblasts without affecting the proliferation of neural progenitor cell (NPCs) in the SVZ. The present study revisits these findings, using a clinically more relevant transgenic rat model of late onset HD (tgHD rats) carrying the human HTT gene with 51 CAG repeats and mimicking many of the neuropathological features of HD seen in patients. We demonstrate that cell proliferation is reduced in the SVZ and OB of tgHD rats compared to WT rats. In the OB of tgHD rats, although cell survival was reduced, the frequency of neuronal differentiation was not altered in the granule cell layer (GCL) compared to the WT rats. However, an increased frequency of dopamenergic neuronal differentiation was noticed in the glomerular layer (GLOM) of tgHD rats. Besides this, we observed a selective proliferation of neuroblasts in the adjacent striatum of tgHD rats. There was no evidence for neuronal maturation and survival of these striatal neuroblasts. Therefore, the functional role of these invading neuroblasts still needs to be determined, but they might offer an endogenous alternative for stem or neuronal cell transplantation strategies.

Distinct Effects of Chronic Dopaminergic Stimulation on Hippocampal Neurogenesis and Striatal Doublecortin Expression in Adult Mice

“…At present, it is still an open question whether DCX + neuroblasts or newly generated neurons within the striatum evade from the adjacent SVZ or are locally generated from an endogenous progenitor pool within the striatal parenchyma. Interestingly and similar to the post-mortem analysis in humans, we observed an increased number of DCX + neuroblasts in the striatum adjacent to the SVZ in transgenic mouse and rat models of Huntington's disease (HD) suggesting that the damaged striatum may attract to some extent immature neuroblasts from the adjacent SVZ (Kohl et al, 2010 ; Kandasamy et al, 2015 ). However, it is important to note that the lesioned striatum in PD models even after stimulation with growth factors such as the epidermal growth factor or the fibroblast growth factor-2 failed to provide a sufficient stimulus for immature DCX + neuroblasts to obtain a mature neuronal phenotype (Winner et al, 2008 ).…”

Concise Review: The Use of Stem Cells for Understanding and Treating Huntington's Disease

“…Within the QA‐lesioned striatum, a subpopulation of newly generated cells express markers for immature and mature neurons, including the phenotypic marker of MSNs, dopamine‐, and cAMP‐regulated phosphoprotein‐32 (DARPP32) and interneurons, parvalbumin, and neuropeptide Y . Interestingly, SVZ‐derived neuroblasts have been reported to migrate to the striatum in the late onset rat transgenic model of HD correlating with the observations made in the QA lesion model. The late onset transgenic rat model mimics many of the neuropathological features of HD seen in patients, supporting the concept that the lack of SVZ neurogenesis seen in transgenic mouse models is due to a limitation in construct validity.…”

Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition

“…The specific effects of mHTT on postnatal neurogenesis in symptomatic HD models are somewhat controversial. While some studies did not find changes in SVZ proliferation or differentiation in R6/2 or YAC128 mice ( 74 , 75 ), others detected reduced levels of neurogenesis in the R6/2 model ( 76 , 77 ) and aberrant neuronal differentiation in tgHD rats ( 78 ). In HD patients, cell proliferation in the SVZ is increased, which correlates with disease grade ( 79 ).…”