Abstract
Spinocerebellar ataxia type 1 (SCA1) is a fatal, autosomal-dominantly inherited neurodegenerative disorder characterised by progressive loss of motor coordination and balance, termed ataxia. SCA1 pathology is caused by expansion of an unstable cytosine-adenine-guanine (CAG; Q) trinucleotide repeat, encoding glutamine, in the ataxin-1 gene. The accumulation of mutant ataxin-1 protein aggregates leads to neuronal dysfunction and neuronal loss in the cerebellum, brainstem and spinal cord. Currently, no disease-modifying therapies exist for SCA1, as the underlying disease mechanism is not fully understood.
One treatment that has shown long-term beneficial effects for patients with ataxia, though not specifically SCA1 patients, is exercise. Exercise alleviates motor disturbances, reduces fall frequency, increases gait speed and improves quality of daily-living in human patients with ataxia. Consistent with these findings, forced exercise alleviates motor coordination deficits, reduces cerebellar Purkinje neuron (PN) loss and increases longevity in SCA1 mice, which mimic hallmarks of human SCA1 pathophysiology. However, the consequence of exercise on the abnormal cerebellar circuitry exhibited by SCA1 mice including, retraction of excitatory climbing fibres (CFs) along PN dendrites and PN dendritic atrophy has not been investigated.
The aims of this study were to determine whether voluntary exercise could alleviate motor deficits and cerebellar circuitry abnormalities in SCA1 mice. To achieve this, four-week-old SCA1 154Q/2Q and wild-type (WT) mice were separated into exercising (E) and non-exercising (NE) groups, and individually housed with or without a voluntary running wheel for 4 weeks. Thereafter, motor function and cerebellar circuitry abnormalities were examined. The results show voluntary exercise improves motor function on an accelerating rotarod and restores WT-like hind-limb clasping behaviour in SCA1 154Q/2Q mice. Meanwhile, CF regression along the PN dendrites was only partially rescued by voluntary exercise in SCA1 154Q/2Q mice, suggesting an alternative pathway may contribute to the recovered motor behaviours observed in SCA1 154Q/2Q E mice.
Brain-derived neurotrophic factor (BDNF) is a potential candidate for recovering motor behaviour, as administering exogenous BDNF improves motor function on an accelerating rotarod in SCA1 mice, and it is well-established that BDNF levels in the brain (and cerebellum) are enhanced following exercise. Here, whole cerebellar BDNF levels (measured using an ELISA) were similar between SCA1 154Q/2Q NE and WT NE mice, and significantly elevated in SCA1 154Q/2Q mice following voluntary exercise. In contrast to the BDNF ELISA findings, BDNF expression levels in areas where molecular layer interneurons (MLIs) reside (assessed using fluorescent immunohistochemistry) were significantly enhanced in SCA1 154Q/2Q NE mice when compared to WT NE mice, and significantly reduced following voluntary exercise in SCA1 154Q/2Q mice.
Basket cells (BCs, a type of MLI) form a well-characterised, complex inhibitory synapse with the PN axon initial segment which regulates PN firing. Thus, the influence voluntary exercise has on BC morphology was assessed next, using fluorescent immunohistochemistry. No overt differences in BC pinceau morphology or BC-PN connectivity were observed between 9-week-old SCA1 154Q/2Q NE and WT NE mice. Following voluntary exercise, SCA1 154Q/2Q E mice displayed smaller BC pinceau and fewer BC-PN inhibitory connections, when compared to SCA1 154Q/2Q NE mice. Given PN firing is reportedly reduced in SCA1 mice shrinkage of the inhibitory BC pinceau and removal of BC-PN connections in SCA1 154Q/2Q E mice may increase (or normalise) PN firing, providing a plausible explanation for the recovered motor performance. Although further work is needed to establish a causal link between BDNF, exercise and the MLI synaptic changes the results here provide an exciting new mechanism for exercise-induced motor recovery. If successful, this work could provide a new avenue for pharmacological treatment options for SCA1, especially for patients whose ataxia has progressed to a stage where they can no longer exercise.