Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease

Abstract

In Huntington's disease (HD), cognitive symptoms and cellular dysfunction precede the onset of classical motor symptoms and neuronal death in the striatum and cortex by almost a decade. This suggests that the early cognitive deficits may be due to a cellular dysfunction rather than being a consequence of neuronal loss. Abnormalities in dendritic spines are described in HD patients and in HD animal models. Available evidence indicates that altered spine and synaptic plasticity could underlie the motor as well as cognitive symptoms in HD. However, the exact kinetics of spine alterations and plasticity in HD remain unknown. We used long-term two-photon imaging through a cranial window, to track individual dendritic spines in a mouse model of HD (R6/2) as the disease progressed. In vivo imaging over a period of 6 weeks revealed a steady decrease in the density and survival of dendritic spines on cortical neurons of R6/2 mice compared with control littermates. Interestingly, we also observed increased spine formation in R6/2 mice throughout the disease. However, the probability that newly formed spines stabilized and transformed into persistent spines was greatly reduced compared with controls. In cultured neurons we found that mutant huntingtin causes a loss, in particular of mature spines. Furthermore, in R6/2 mice, aggregates of mutant huntingtin associate with dendritic spines. Alterations in dendritic spine dynamics, survival, and density in R6/2 mice were evident before the onset of motor symptoms, suggesting that decreased stability of the cortical synaptic circuitry underlies the early symptoms in HD.

A close look at brain dynamics: Cells and vessels seen by in vivo two-photon microscopy

“…Besides monitoring of physiological synaptic responsiveness, 2-PM has been applied to measure structural plasticity of dendritic spines in different mouse models of pathological conditions, such as Alzheimer's disease (Bittner et al, 2012), Rett syndrome (Landi et al, 2011), Huntington's disease (Murmu et al, 2013), the syndrome caused by methyl-CpG-binding protein-2 duplication (Jiang et al, 2013), or brain ischemia (Sigler and Murphy, 2010).…”

The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease

“…Early neuropathological features of HD include perturbed corticostriatal synaptic function and connectivity (Miller and Bezprozvanny, 2010; Milnerwood and Raymond, 2007; Milnerwood and Raymond, 2010; Murmu et al, 2013; Orth et al, 2010; Schippling et al, 2009), eventually leading to overt neurodegeneration of medium spiny neurons (MSNs) in the striatum (Myers et al, 1988; Vonsattel and DiFiglia, 1998). Perturbed stability of synaptic spines has been suggested to underlie the development of HD symptoms (Bezprozvanny and Hiesinger, 2013; Murmu et al, 2013; Ryskamp et al, 2016).…”

“…Perturbed stability of synaptic spines has been suggested to underlie the development of HD symptoms (Bezprozvanny and Hiesinger, 2013; Murmu et al, 2013; Ryskamp et al, 2016). In recent studies, we demonstrated that post-synaptic dendritic spines of MSNs are lost in aged corticostriatal co-cultures established from YAC128 mice (Wu et al, 2016).…”

Hyperkinetic disorders and loss of synaptic downscaling

“…Recently, a novel imaging technique was used to study spine alteration kinetics associated with plastic changes in the R6/2 genetic model of HD 26 . In R6/2 mice the probability that newly formed spines will stabilize and transform into persistent spines is greatly reduced compared to that in controls, and in R6/2 mice, aggregates of mutant Htt are localized to dendritic spines.…”