Cerebellar neuronal dysfunction accompanies early motor symptoms in spinocerebellar ataxia type 3

Abstract

Spinocerebellar Ataxia Type 3 (SCA3) is an adult-onset, progressive ataxia. SCA3 presents with ataxia before any gross neuropathology. A feature of many cerebellar ataxias is aberrant cerebellar output that contributes to motor dysfunction. We examined whether abnormal cerebellar output was present in the CMVMJD135 SCA3 mouse model and, if so, whether it correlated with the disease onset and progression. In vivo recordings showed that the activity of deep cerebellar nuclei neurons, the main output of the cerebellum, was altered. The aberrant activity correlated with the onset of ataxia. However, although the severity of ataxia increased with age, the severity of the aberrant cerebellar output was not progressive. The abnormal cerebellar output, however, was accompanied with non-progressive abnormal activity of their upstream synaptic inputs, the Purkinje cells. In vitro recordings indicated that alterations in both intrinsic Purkinje cell pacemaking and in their synaptic inputs contributed to abnormal Purkinje cell activity. These findings implicate abnormal cerebellar physiology as an early, consistent contributor to pathophysiology in SCA3, and suggest that the aberrant cerebellar output could be an appropriate therapeutic target in SCA3.

Disrupted cerebellar structural connectome in spinocerebellar ataxia type 3 and its association with transcriptional profiles

“…Synaptic loss was observed in cerebellum and brainstem of SCA3 patients in PET imaging 60 , and also in other types of hereditary ataxia in the postmortem neuropathology estimation 61,62 . Synapse is responsible for signal passing between neurons, and its abnormality leads to cerebellar neuronal dysfunction and further impacts the output to cerebrum to accurately encode motor-related events 63 . The GO term such as DNA repair is a subset of the term, DNA metabolic process, and RNA splicing is a subset of the term, RNA metabolic process.…”

Influence of data sampling methods on the representation of neural spiking activity in vivo

“…In mouse models of cerebellar movement disorders, the source of cerebellar dysfunction is consistent with changes in the firing rate and/or pattern of Purkinje cell and cerebellar nuclei neuron firing. 7 , 13 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 Altered basal firing properties have also been reported in the thalamus, 11 basal ganglia, 60 and cerebral cortex 61 during abnormal movements, and during seizures. 62 , 63 The task of recording firing activity from neurons in the awake condition has many challenges and limitations, particularly in movement disorders, as the awake animal may frequently perform involuntary actions that can destabilize neural recordings.…”