Background Huntington's disease is a neurodegenerative disease caused by an expansion of CAG triplets in the gene huntingtin. This mutation generates an N-terminal polyQ expansion within the HTT protein, which leads to a broad array of cellular and synaptic dysfunction. Many of these deficits precede the death of striatral and cortical neurons. Recent evidence implicates that spiny synapses are important substrate of HD pathogenesis altered spine dynamics and reduced spine density are some of the early manifestation of HD. The membrane-associated guanylate kinase PSD-95 is highly enriched at excitatory synapses and organises the molecular architecture of synapses and regulates interactions between glutamate receptors and downstream-signalling molecules. Interestingly, PSD-95 interacts with HTT protein and the presence of pathological polyQ expansion weakens this interaction. Additionally, decreased level of PSD-95 was observed in HD.
Aims We propose that the synaptic decrease and redistribution of PSD-95 contributes impaired spine dynamics and reduced spine number in a R6/2 mouse model of HD.
Methods/techniques Therefore, we first delivered AAV viral vector expressing PSD-95 into somatosensory cortex then we used time-lapse two-photon imaging through a cranial window to track individual dendritic spines in HD mice as the disease is progressed.
Results Repetitive imaging of apical dendrites of cortical neurons revealed impaired stabilisation of newly formed spines and reduced spine density in R6/2 mice compared with WT controls. We also found that genetic modulation of PSD-95 beneficially influences dendritic spine turnover and the preservation of synaptic structure in HD mice. We also performed morphological assessment to visualise neurons and their processes in PSD-95-delivered and vehicle HD mice.
Conclusions Genetic modulation of PSD-95 might advantageous for early symptoms in HD via stabilising dendritic spines and via promotion of spine maturation.
- in vivo imaging
- mouse model of HD
- dendritic spines
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