Abstract
Late-onset neurodegenerative diseases are characterized by neurological symptoms and progressive neuronal death. Accumulating evidence suggests that neuronal dysfunction, rather than neuronal death, causes the symptoms of neurodegenerative diseases. However, the mechanisms underlying the dysfunction that occurs prior to cell death remain unclear. To investigate the synaptic basis of this dysfunction, we employed in vivo two-photon imaging to analyse excitatory postsynaptic dendritic protrusions. We used Sca1154Q/2Q mice, an established knock-in mouse model of the polyglutamine disease spinocerebellar ataxia type 1 (SCA1), which replicates human SCA1 features including ataxia, cognitive impairment, and neuronal death. We found that Sca1154Q/2Q mice exhibited greater synaptic instability than controls, without synaptic loss, in the cerebral cortex, where obvious neuronal death is not observed, even before the onset of distinct symptoms. Interestingly, this abnormal synaptic instability was evident in Sca1154Q/2Q mice from the synaptic developmental stage, and persisted into adulthood. Expression of synaptic scaffolding proteins was also lower in Sca1154Q/2Q mice than controls before synaptic maturation. As symptoms progressed, synaptic loss became evident. These results indicate that aberrant synaptic instability, accompanied by decreased expression of scaffolding proteins during synaptic development, is a very early pathology that precedes distinct neurological symptoms and neuronal cell death in SCA1.
Highlights
Sca1154Q/2Q mice develop motor learning impairment before any obvious Purkinje cell death occurs or nuclear inclusions form in the cerebellum[5]
Dendritic protrusions were classified into spines and filopodia according to their morphology, because filopodia are less stable than spines, and their density decreases with development[9]
Understanding the mechanisms of the neuronal dysfunction that precedes behavioural impairments and neuronal death is a longstanding challenge in neurodegenerative diseases such as SCA1
Summary
Sca1154Q/2Q mice develop motor learning impairment before any obvious Purkinje cell death occurs or nuclear inclusions form in the cerebellum[5]. Clinical studies have demonstrated that neuronal death is most prominent in the cerebellum, whereas little occurs in the cerebral cortex and hippocampus, despite the presence of cognitive impairments in patients with SCA16. These lines of evidence suggest that neuronal dysfunction, preceding cell death, causes subsequent behavioural impairments in the pathogenesis of SCA1; the mechanisms underlying the dysfunction remain unclear. Our findings demonstrate that aberrant synaptic instability accompanied by a reduction in the expression of scaffolding proteins in affected neurons appears during synaptic development in SCA1 mice These results suggest that deficits in neuronal circuitry development may underlie subsequent behavioural and neurological impairments in late-onset neurodegenerative diseases
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