B23 Mutant Huntingtin Causes Loss Of Mechanisms Underlying Long-term Memory Storage In The Brain Revealed By Two-photon Imaging

Abstract

<h3>Background</h3> A key question in Huntington’s disease (HD) is what underlies the early cognitive deficits that precede the motor symptoms and the characteristic neuronal death observed in HD. The mechanisms underlying cognitive symptoms in HD remain unknown. Dendritic spine pathology and abnormal synaptic plasticity (which is found in post-mortem HD brain and in HD models prior to neurodegeneration) is thought to underlie the early cognitive symptoms observed in HD, however, direct in vivo evidence is lacking. Although HD is a genetically inherited disorder, it is affected by environmental factors inducing sensory, cognitive and motor stimulations. Experience-dependent synaptic plasticity caused by mechanisms such as LTP or novel sensory experience potentiates synaptic strength, enhances new dendritic spine formation and stabilisation and may contribute to normal cognitive processes, such as learning and memory. <h3>Aims</h3> The aim of this study is to investigate the mechanisms underlying early cognitive symptoms in Huntington’s disease. <h3>Methods/techniques</h3> We have followed individual dendritic spines as the disease progressed in HD model R6/2 using two-photon laser scanning microscopy. <h3>Results/outcome</h3> Using two-photon microscopy as the disease progressed in R6/2 HD model, we show that under baseline condition the cortical neuronal circuitry is highly unstable (already at the pre-symptomatic phase) in the R6/2 mice that led to a progressive loss of persistenttype mature spine in these mice compared to the wild-type littermates. Further, our results indicate that mutant <i>huntingtin </i>was directly involved in the loss of particularly the persistent-type mature spines, which are the site of long-term memory storage in the brain. We further observed that the pathological processes of HD interfered with the normal experience-dependent plasticity of dendritic spines in the R6/2 model. Six weeks of two-photon <i>in vivo</i>imaging before and after whisker trimming revealed that sensory deprivation exacerbated loss of persistent-type, stable spines in the R6/2 mice compared to wild-type littermates. In addition, sensory deprivation led to impaired transformation of newly generated spines into persistent spines in R6/2 mice. As a consequence, reduced synaptic density was observed in their barrel cortical neurons. <h3>Conclusions</h3> Our findings suggests that mutant <i>huntingtin </i>is implicated in the loss of mechanisms underlying long-term memory storage in the brain and in maladaptive synaptic plasticity, which could be one of the plausible mechanisms underlying early cognitive deficits in HD.