Hippocampal mitochondrial dysfunction and psychiatric-relevant behavioral deficits in spinocerebellar ataxia 1 mouse model

Abstract

Spinocerebellar ataxia 1 (SCA1) is a devastating neurodegenerative disease associated with cerebellar degeneration and motor deficits. However, many patients also exhibit neuropsychiatric impairments such as depression and apathy; nevertheless, the existence of a causal link between the psychiatric symptoms and SCA1 neuropathology remains controversial. This study aimed to explore behavioral deficits in a knock-in mouse SCA1 (SCA1 154Q/2Q) model and to identify the underlying neuropathology. We found that the SCA1 mice exhibit previously undescribed behavioral impairments such as increased anxiety-and depressive-like behavior and reduced prepulse inhibition and cognitive flexibility. Surprisingly, non-motor deficits characterize the early SCA1 stage in mice better than does ataxia. Moreover, the SCA1 mice exhibit significant hippocampal atrophy with decreased plasticity-related markers and markedly impaired neurogenesis. Interestingly, the hippocampal atrophy commences earlier than the cerebellar degeneration and directly reflects the individual severity of some of the behavioral deficits. Finally, mitochondrial respirometry suggests profound mitochondrial dysfunction in the hippocampus, but not in the cerebellum of the young SCA1 mice. These findings imply the essential role of hippocampal impairments, associated with profound mitochondrial dysfunction, in SCA1 behavioral deficits. Moreover, they underline the view of SCA1 as a complex neurodegenerative disease and suggest new avenues in the search for novel SCA1 therapies. Spinocerebellar ataxia type 1 (SCA1) is a lethal dominantly-inherited neurodegenerative disease, caused by CAG repeat expansion (> 40 CAG repeats) in the ataxin-1 encoding gene (ATXN1) 1. This mutation results in ataxin-1 protein toxicity and aggregation which leads, in particular, to cerebellar and brainstem degeneration 2 , although ATXN1 is widely expressed throughout the brain 1. SCA1 symptoms usually appear in early middle-age and include motor incoordination and gait deficits followed by muscular and swallowing problems in the later stages of the disease 3. However, in a similar way to other types of spinocerebellar ataxias (SCAs), over 50% of patients also demonstrate neuropsychiatric issues 4-7 including cognitive impairments, anxiety, apathy and depression 7-9. Interestingly, in contrast to progressive ataxia, the psychiatric impairments tend to remain relatively stable over time 8. Although they are often overlooked, they profoundly impact the quality of life and health outcomes of patients with SCA1 and related diseases 9. However, the question of whether these psychiatric impairments are causally linked to SCA1 neuropathology, or if they represent an emotional response to SCA1 diagnosis and subsequent physical disability, remains controversial 9 .

Identifying Disease Signatures in the Spinocerebellar Ataxia Type 1 Mouse Cortex

“…We analyzed SCA1 KI mouse brain tissue at 12 and 30 weeks, as these are known to represent mid- and late stages of SCA1 disease progression in the mouse cerebellum, and are time points at which motor and cognitive impairment is observed in SCA1 KI mice [ 10 , 40 , 41 ]. At 12 weeks, there is significant astro- and micro-gliosis observed in the cerebellum [ 40 ], as well as motor and cognitive behavioral deficits, including impaired spatial learning by Morris Water Maze, and impaired learning and memory by conditioned fear response [ 10 , 41 ]. At 30 weeks, these phenotypes are more severe, and cerebellar PC loss is observed as well [ 10 , 41 ].…”

“…At 12 weeks, there is significant astro- and micro-gliosis observed in the cerebellum [ 40 ], as well as motor and cognitive behavioral deficits, including impaired spatial learning by Morris Water Maze, and impaired learning and memory by conditioned fear response [ 10 , 41 ]. At 30 weeks, these phenotypes are more severe, and cerebellar PC loss is observed as well [ 10 , 41 ].…”

Mood alterations in mouse models of Spinocerebellar Ataxia type 1

“…ATXN1 is expressed throughout the brain, including hippocampus, cortex, cerebellum, and hypothalamus, and it is possible that pathology caused by polyQ expanded ATXN1 in any of these regions contributes to SCA1-like mood alterations 16 , 48 , 56 . Indeed, a recent study implicated hippocampal dysfunction in neurobehavioral deficits described in SCA1 knock-in mice 57 . Future studies using conditional SCA1 knock-in mice or viral-mediated approaches, in which polyQ ATXN1 can be selectively expressed or deleted in distinct brain regions, will be able to identify the anatomical substrates of mood alterations in SCA1.…”

Complex Interplay of Genes Underlies Invasiveness in Fibrosarcoma Progression Model

“…Parametric statistical analyses were extended by permutational (hypothesis testing) or bias-corrected and accelerated bootstrap [ 46 ] (estimation of 95% confidence intervals) techniques (10,000–21,000 permutations/resamplings), which do not rely on assumptions of parametric methods and give reliable results even for small sample sizes. Comparisons between groups were performed by permutational ANOVA followed by permutational t-test (exact if N < 11, Monte-Carlo otherwise) with false discovery rate correction for multiple comparisons [ 47 ] as a post hoc, both using predictmeans‘ R package [ 48 ] and our previously used and published R scripts [ 49 , 50 ]. Heteroscedastic residuals were stabilised by appropriate data transformation.…”