Sex-specific alterations of Purkinje cell firing in Sgce knockout mice and correlations with myoclonus.

Myoclonus is a hyperkinetic movement disorder characterized by sudden, brief, involuntary jerks of single or multiple muscles. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Myoclonus-dystonia (M-D) or DYT11 dystonia is an early-onset genetic disorder characterized by subcortical myoclonus and less pronounced dystonia. DYT11 dystonia is the primary genetic M-D caused by loss of function mutations in SGCE, which codes for ε-sarcoglycan. Sgce knockout (KO) mice model DYT11 dystonia and exhibit myoclonus, motor deficits, and psychiatric-like behaviors. Neuroimaging studies show abnormal cerebellar activity in DYT11 dystonia patients. Acute small hairpin RNA (shRNA) knockdown of Sgce mRNA in the adult cerebellum leads to motor deficits, myoclonic-like jerky movements, and altered Purkinje cell firing. Whether Sgce KO mice show similar abnormal Purkinje cell firing as the acute shRNA knockdown mice is unknown. We used acute cerebellar slice recording in Sgce KO mice to address this issue. The Purkinje cells from Sgce KO mice showed spontaneous and intrinsic excitability changes compared to the wild-type (WT) mice. Intrinsic membrane properties were not altered. The female Sgce KO mice had more profound alterations in Purkinje cell firing than males, which may correspond to the early onset of the symptoms in female human patients and more pronounced myoclonus in female KO mice. Our results suggest that the abnormal Purkinje cell firing in the Sgce KO mice contributes to the manifestation of the myoclonus and other motor symptoms in DYT11 dystonia patients.