Alleviation of cerebellar impairment, cognitive decline, and depression by a chlorzoxazone-folic acid combination in a Huntington's disease transgenic mouse model

Huntington's disease (HD) is a hereditary neurodegenerative condition, passed down in an autosomal dominant manner, characterized by the gradual decline of motor functions, such as chorea, along with psychiatric symptoms and cognitive deterioration. In HD, the striatum is the main area impacted, although cerebellar atrophy has also been observed independently of striatal degeneration. Consequently, HD patients may exhibit symptoms consistent with cerebellar cognitive affective syndrome (CCAS) due to cerebellar involvement. CCAS manifestations have been noted in various rodent models of motor dysfunctions linked to cerebellar atrophy. Previous research has identified anxiety, memory deficits, and depressive-like behavior in the YAC128 transgenic murine model of HD. This investigation examines the effects of prolonged administration of the small-conductance calcium-activated potassium channel (SK channel) positive modulator chlorzoxazone (CHZ), both alone and in combination with folic acid (FA), on cerebellar Purkinje cell (PC) electrophysiology and morphology, along with locomotor and memory decline and emotional state changes in YAC128 mice. The findings indicate that both CHZ alone and the mixture of CHZ and FA similarly ameliorated cerebellar-specific deficits, encompassing the precision of PC electrophysiological activity and beam walk performance in YAC128 mice. However, solely the mixture of CHZ and FA significantly alleviated depressive-like symptoms and improved recognition memory. These findings imply that a therapeutic approach addressing both motor and cognitive-affective deficits is essential for the holistic management of movement disorders associated with cerebellar atrophy, including HD.