Dendritic spine pathology and deficits in experience‐dependent dendritic plasticity in R6/1 Huntington's disease transgenic mice

Abstract

Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG repeat expansion coding for an expanded polyglutamine tract in the huntingtin protein. Dendritic abnormalities occur in human HD patients and in several transgenic mouse models of the disease. In this study, we examine, for the first time, dendrite and spine pathology in the R6/1 mouse model of HD, which mimics neurodegeneration seen in human HD. Enriching the environment of HD transgenic mice delays the onset of symptoms, so we also examine the effects of enrichment on dendrite pathology. Golgi-impregnated tissue from symptomatic R6/1 HD mice reveals a decrease in dendritic spine density and dendritic spine length in striatal medium spiny neurons and cortical pyramidal neurons. HD also causes a specific reduction in the proportion of bifurcated dendritic spines on basal dendrites of cortical pyramidal neurons. No differences in soma size, recurving distal dendrites, or dendritic branching were observed. Although home-cage environmental enrichment from 1 to 8 months of age increases spine density in wild-type mice, it has no effect on the spine pathology in HD mice. These results show that dendritic spine pathology in R6/1 HD mice resembles degenerative changes seen in human HD and in other transgenic mouse models of the disease. We thus provide further evidence that the HD mutation disrupts the connectivity in both neostriatum and cerebral cortex, which will contribute to motor and cognitive disease symptoms. Furthermore, we demonstrate that Huntington's disease pathology interferes with the normal plastic response of dendritic spines to environmental enrichment.

Rapid Morphologic Plasticity of Peri-Infarct Dendritic Spines After Focal Ischemic Stroke

“…In accordance with previous estimates of pyramidal neuron spine length assessed by Golgi or virally based labeling methods, [27][28][29][30] the average length of dendritic spines in the control primary, secondary motor, and contralateral barrel cortex was 1.29Ϯ0.05, 1.16Ϯ0.04, and 1.20Ϯ0.05 m, respectively ( Figure 2B). Our quantitative analysis revealed that spine length varied significantly as a function of time after stroke (F 3,48 ϭ3.94, Pϭ0.013) and distance from the site of infarction (F 2,48 ϭ13.14, PϽ0.0001).…”

Abnormalities of Neurogenesis in the R6/2 Mouse Model of Huntington's Disease Are Attributable to theIn VivoMicroenvironment

“…The finding of abnormal morphology of newborn neurons in R6/2 mice is consistent with the reduced sprouting seen in the sciatic nerve of R6/2 mice (Ribchester et al, 2004) and abnormal dendritic branching seen in medium spiny striatal neurons of R6/2 mice (Spires et al, 2004a) and HD patients (Ferrante et al, 1991). Iannicola et al (2000) reported that hippocampal neurites in a transgenic HD mouse are shortened, and this study supports and extends these findings.…”

Brain-Derived Neurotrophic Factor Restores Synaptic Plasticity in a Knock-In Mouse Model of Huntington's Disease

“…The deficits in actin polymerization found in Hdh Q111 mice also provide a possible explanation for the abnormal spine morphology found in striatal and cortical neurons of HD transgenic mouse models (Guidetti et al, 2001;Klapstein et al, 2001;Spires et al, 2004b) and in HD patients (Graveland et al, 1985;Ferrante et al, 1991). The actin cytoskeleton regulates the shape of dendritic spines (Fischer et al, 2000;Star et al, 2002), at least in developing tissue, and deficiencies in activity-dependent F-actin assembly would be expected to cause aberrant morphology.…”