Mood alterations in mouse models of Spinocerebellar Ataxia type 1

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by abnormal expansion of glutamine-encoding CAG repeats in the Ataxin-1 (ATXN1) gene. SCA1 is characterized by progressive motor deficits, cognitive decline, and mood changes including anxiety and depression, with longer number of repeats correlating with worse disease outcomes. While mouse models have been very useful in understanding etiology of ataxia and cognitive decline, our understanding of mood symptoms in SCA1 has lagged. It remains unclear whether anxiety or depression stem from an underlying brain pathology or as a consequence of living with an untreatable and lethal disease. To increase our understanding of the etiology of SCA1 mood alterations, we used the elevated-plus maze, sucrose preference and forced swim tests to assess mood in four different mouse lines. We found that SCA1 knock-in mice exhibit increased anxiety that correlated with the length of CAG repeats, supporting the idea that underlying brain pathology contributes to SCA1-like anxiety. Additionally, our results support the concept that increased anxiety is caused by non-cerebellar pathology, as Purkinje cell specific SCA1 transgenic mice exhibit decreased anxiety-like behavior. Regarding the molecular mechanism, partial loss of ATXN1 may play a role in anxiety, based on our results for Atxn1 haploinsufficient and null mice.

The cerebellum and anxiety

“…Studies on spinocerebellar ataxia (SCA) rodent models also support a cerebellar role in anxiety behavior. SCA models are generally characterized by abnormal expansion of CAG repeats in genes that lead to an ataxic pathology due to neurodegeneration in the cerebellum, often in Purkinje cells (Boy et al, 2009(Boy et al, , 2010Kelp et al, 2013;Asher et al, 2021;Bohne et al, 2022). Anxiety behavior is one of the most studied behaviors amongst the various non-sensorimotor impairments also observed in SCA models, beyond their characteristic ataxic phenotype.…”

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

“…Since hippocampal pathology precedes the development of significant cerebellar dysfunction [ 4 ] and, as Tichanek [ 7 ] pointed out, cerebellar impairment can induce opposite changes in behavior compared to hippocampal dysfunction, some behavioral abnormalities can be reduced with age and progress of the cerebellar component of the disease. Furthermore, the results of this test are controversial in general, since both reduced and increased sucrose preference in SCA1 mice have been previously reported [ 4 , 23 ]. In cerebellar mutant mice, depressive- and anxiety-like behavior and anhedonia on one hand and reduced anxiety on the other hand can be manifested.…”

“…In cerebellar mutant mice, depressive- and anxiety-like behavior and anhedonia on one hand and reduced anxiety on the other hand can be manifested. The first occurs in the case of significant extracerebellar neuropathology, the latter rather in mice with selective cerebellar damage [ 4 , 23 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ].…”

“…In patients with SCA1, oculomotor disorders, bulbar syndrome, and respiratory disorders have also been reported [ 16 ]. Nevertheless, SCA1 also leads to neuropsychiatric problems, including cognitive impairment, anxiety, apathy, and depression, which can be seen in both human and mouse models [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. In addition, changes in functions associated with hippocampal plasticity have been described [ 9 , 25 , 26 ].…”

Memantine Disrupts Motor Coordination through Anxiety-like Behavior in CD1 Mice

“…The time spent in closed arms was recorded. The maze was cleaned with 70% ethanol before each trial [18].…”