Cerebellar neuronal dysfunction accompanies early motor symptoms in Spinocerebellar Ataxia Type 3 and is partially alleviated upon chronic citalopram treatment

Spinocerebellar ataxia type 3 (SCA3) is an adult-onset, progressive ataxia with no current disease modifying treatments. SCA3 patients have mild degeneration of the cerebellum, a brain area involved in motor coordination and maintenance of balance, as well as of the brainstem, of the spinal cord and of other movement-related subcortical areas. However, both SCA3 patients and SCA3 mouse models present clinical symptoms before any gross pathology is detectable, which suggests neuronal dysfunction precedes neurodegeneration, and opens an opportunity for therapeutic intervention. Such observations also raise the question of what triggers these abnormal motor phenotypes. Purkinje cells are the major computational unit within the cerebellum and are responsible for facilitating coordinated movements. Abnormal Purkinje cell activity is sufficient to cause ataxia. In this study, we show that the CMVMJD135 mouse model of SCA3 has dysfunctional deep cerebellar nuclei and Purkinje cells. Both cell types have increased irregularity as measured by inter-spike interval coefficient of variation. Purkinje cell dysfunction is likely a combination of intrinsic and extrinsic (synaptic) dysfunction. Interestingly, Citalopram, a selective serotonin reuptake inhibitor previously shown to alleviate disease in CMVMJD135 mice, also improved cerebellar neuron function in the CMVMJD135 mouse model. Specifically, we found that Purkinje cell dysfunction when synaptic transmission is intact was alleviated with citalopram treatment, however, intrinsic Purkinje cell dysfunction was not alleviated. Altogether, our findings suggest that cerebellar neuronal dysfunction contributes to the onset of SCA3 motor dysfunction and that citalopram, while effective at alleviating the motor phenotype, does not restore Purkinje cell intrinsic activity in SCA3. A novel therapeutic approach that combines citalopram with another therapeutic that targets this intrinsic dysfunction in a complementary manner might further reduce disease burden in SCA3. ### Competing Interest Statement The authors have declared no competing interest.