Many patients with spinocerebellar ataxia (SCA) suffer from diverse neuropsychiatric issues, including memory impairments, apathy, depression, or anxiety. These neuropsychiatric aspects contribute per se to the reduced quality of life and worse prognosis. However, the extent to which SCA-related neuropathology directly contributes to these issues remains largely unclear. Behavioral profiling of various SCA mouse models can bring new insight into this question. This paper aims to synthesize recent findings from behavioral studies of SCA patients and mouse models. The role of SCA neuropathology for shaping psychiatric-like impairments may be exemplified in mouse models of SCA1. These mice evince robust cognitive impairments which are shaped by both the cerebellar as well as out-of-cerebellar pathology. Although emotional-related alternations are also present, they seem to be less robust and more affected by the specific distribution and character of the neuropathology. For example, cerebellar-specific pathology seems to provoke behavioral disinhibition, leading to seemingly decreased anxiety, whereas complex SCA1 neuropathology induces anxiety-like phenotype. In SCA1 mice with complex neuropathology, some of the psychiatric-like impairments are present even before marked cerebellar degeneration and ataxia and correlate with hippocampal atrophy. Similarly, complete or partial deletion of the implicated gene (Atxn1) leads to cognitive dysfunction and anxiety-like behavior, respectively, without apparent ataxia and cerebellar degeneration. Altogether, these findings collectively suggest that the neuropsychiatric issues have a biological basis partially independent of the cerebellum. As some neuropsychiatric issues may stem from weakening the function of the implicated gene, therapeutic reduction of its expression by molecular approaches may not necessarily mitigate the neuropsychiatric issues.

Department of Pathological Physiology Faculty of Medicine in Pilsen Charles University alej Svobody 1655 76 323 00 Plzen Czech Republic

Laboratory of Neurodegenerative Disorders Biomedical Center Faculty of Medicine in Pilsen Charles University alej Svobody 1655 76 323 00 Plzen Czech Republic

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Experimental Treatment with Edaravone in a Mouse Model of Spinocerebellar Ataxia 1