Cerebellar Diseases Research Articles

Cerebellar nuclei cells produce distinct pathogenic spike signatures in mouse models of ataxia, dystonia, and tremor.

The cerebellum contributes to a diverse array of motor conditions, including ataxia, dystonia, and tremor. The neural substrates that encode this diversity are unclear. Here, we tested whether the neural spike activity of cerebellar output neurons is distinct between movement disorders with different impairments, generalizable across movement disorders with similar impairments, and capable of causing distinct movement impairments. Using in vivo awake recordings as input data, we trained a supervised classifier model to differentiate the spike parameters between mouse models for ataxia, dystonia, and tremor. The classifier model correctly assigned mouse phenotypes based on single-neuron signatures. Spike signatures were shared across etiologically distinct but phenotypically similar disease models. Mimicking these pathophysiological spike signatures with optogenetics induced the predicted motor impairments in otherwise healthy mice. These data show that distinct spike signatures promote the behavioral presentation of cerebellar diseases.

The Role of the Human Cerebellum for Learning from and Processing of External Feedback in Non-Motor Learning: A Systematic Review

This review aimed to systematically identify and comprehensively review the role of the cerebellum in performance monitoring, focusing on learning from and on processing of external feedback in non-motor learning. While 1078 articles were screened for eligibility, ultimately 36 studies were included in which external feedback was delivered in cognitive tasks and which referenced the cerebellum. These included studies in patient populations with cerebellar damage and studies in healthy subjects applying neuroimaging. Learning performance in patients with different cerebellar diseases was heterogeneous, with only about half of all patients showing alterations. One patient study using EEG demonstrated that damage to the cerebellum was associated with altered neural processing of external feedback. Studies assessing brain activity with task-based fMRI or PET and one resting-state functional imaging study that investigated connectivity changes following feedback-based learning in healthy participants revealed involvement particularly of lateral and posterior cerebellar regions in processing of and learning from external feedback. Cerebellar involvement was found at different stages, e.g., during feedback anticipation and following the onset of the feedback stimuli, substantiating the cerebellum’s relevance for different aspects of performance monitoring such as feedback prediction. Future research will need to further elucidate precisely how, where, and when the cerebellum modulates the prediction and processing of external feedback information, which cerebellar subregions are particularly relevant, and to what extent cerebellar diseases alter these processes.

Cerebellar dysfunction in rodent models with dystonia, tremor, and ataxia.

Dystonia is a movement disorder characterized by involuntary co- or over-contractions of the muscles, which results in abnormal postures and movements. These symptoms arise from the pathophysiology of a brain-wide dystonia network. There is mounting evidence suggesting that the cerebellum is a central node in this network. For example, manipulations that target the cerebellum cause dystonic symptoms in mice, and cerebellar neuromodulation reduces these symptoms. Although numerous findings provide insight into dystonia pathophysiology, they also raise further questions. Namely, how does cerebellar pathophysiology cause the diverse motor abnormalities in dystonia, tremor, and ataxia? Here, we describe recent work in rodents showing that distinct cerebellar circuit abnormalities could define different disorders and we discuss potential mechanisms that determine the behavioral presentation of cerebellar diseases.

Effectiveness of Vestibular Rehabilitation for Patients with Degenerative Cerebellar Ataxia: A Retrospective Cohort Study.

Many patients with cerebellar ataxia have dizziness caused by oculomotor or peripheral vestibular deficits; however, there is little evidence supporting the use of vestibular rehabilitation for this population. The purpose of this study was to determine whether patients with degenerative cerebellar diseases improve following rehabilitation including vestibular exercises. A secondary aim was to identify variables associated with the outcomes. A retrospective chart review identified 42 ambulatory patients (23 men and 19 women; mean age = 54.5 ± 14.4 years) with cerebellar degeneration. Fourteen patients had ataxia only, twenty had ataxia and oculomotor abnormalities, and eight had ataxia with oculomotor and peripheral vestibular deficits. Patients received customized physical therapy including balance and gait training, as well as gaze stabilization and habituation exercises for vestibular hypofunction and motion-provoked dizziness. Primary outcome measures (Activities-specific Balance Confidence Scale, Tinetti Performance Oriented Mobility Assessment, Dynamic Gait index, and Sensory Organization Test) were evaluated at baseline and discharge. Patients improved (p < 0.05) on all outcome measures. Patients with vestibular deficits were seen for more visits compared to those with gait ataxia only (7.1 vs. 4.8 visits). This study provides evidence that patients with degenerative cerebellar disease improve in balance confidence, fall risk and sensory integration with therapy that includes vestibular rehabilitation.

The Blood Concentration of Metallic Nanoparticles Is Related to Cognitive Performance in People with Multiple Sclerosis: An Exploratory Analysis.

The imbalance in the concentration of metallic nanoparticles has been demonstrated to play an important role in multiple sclerosis (MS), which may impact cognition. Biomarkers are needed to provide insights into the pathogenesis and diagnosis of MS. They can be used to gain a better understanding of cognitive decline in people with MS (pwMS). In this study, we investigated the relationship between the blood concentration of metallic nanoparticles (blood nanoparticles) and cognitive performance in pwMS. First, four mL blood samples, clinical characteristics, and cognitive performance were obtained from 21 pwMS. All participants had relapse-remitting MS, with a score of ≤4.5 points in the expanded disability status scale. They were relapse-free in the three previous months from the day of collection and had no orthopedic, muscular, cardiac, and cerebellar diseases. We quantified the following metallic nanoparticles: aluminum, chromium, copper, iron, magnesium, nickel, zinc, and total concentration. Cognitive performance was measured by mini-mental state examination (MMSE) and the symbol digit modalities test (SDMT). Pearson's and Spearman's correlation coefficients and stepwise linear regression were calculated to assess the relationship between cognitive performance and blood nanoparticles. We found that better performance in SDMT and MMSE was related to higher total blood nanoparticles (r = 0.40; p < 0.05). Also, better performance in cognitive processing speed and attention (SDMT) and mental state (MMSE) were related to higher blood iron (r = 0.44; p < 0.03) and zinc concentrations (r = 0.41; p < 0.05), respectively. The other metallic nanoparticles (aluminum, chromium, copper, magnesium, and nickel) did not show a significant relationship with the cognitive parameters (p > 0.05). Linear regression estimated a significant association between blood iron concentration and SDMT performance. In conclusion, blood nanoparticles are related to cognitive performance in pwMS. Our findings suggest that the blood concentration of metallic nanoparticles, particularly the iron concentration, is a promising biomarker for monitoring cognitive impairment in pwMS.

Differences in spontaneous speech fluency between Parkinson's disease and spinocerebellar ataxia type 3.

The basal ganglia and cerebellum both have a role in speech production although the effect of isolated involvement of these structures on speech fluency remains unclear. The study aimed to assess the differences in the articulatory pattern in patients with cerebellar vs. basal ganglia disorders. A total of 20 individuals with Parkinson's disease (PD), 20 with spinocerebellar ataxia type 3 (SCA3), and 40 controls (control group, CG) were included. Diadochokinesis (DDK) and monolog tasks were collected. The only variable that distinguished SCA3 carriers from the CG was the number of syllables in the monolog, with SCA3 patients of a significantly lower number. For patients with PD, the number of syllables, phonation time, DDK, and monolog were significantly lower than for CG. Patients with PD were significantly worse compared to patients with SCA3 in the number of syllables and phonation time in DDK, and phonation time in monolog. Additionally, there was a significant correlation between the number of syllables in the monolog and the MDS-UPDRS III for participants with PD, and the Friedreich Ataxia Rating Scale for participants with SCA3 suggesting a relationship between speech and general motor functioning. The monolog task is better at discriminating individuals with cerebellar vs. Parkinson's diseases as well as differentiating healthy control and was related to the severity of the disease.

Temporal Relationship between Impairment of Cerebellar Motor Learning and Deterioration of Ataxia in Patients with Cerebellar Degeneration.

Ataxia and impaired motor learning are both fundamental features in diseases affecting the cerebellum. However, it remains unclarified whether motor learning is impaired only when ataxia clearly manifests, nor it is known whether the progression of ataxia, the speed of which often varies among patients with the same disease, can be monitored by examining motor learning. We evaluated motor learning and ataxia at intervals of several months in 40 patients with degenerative conditions [i.e., multiple system atrophy (MSA), Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3), SCA6, and SCA31]. Motor learning was quantified as the adaptability index (AI) in the prism adaptation task and ataxia was scored using the Scale for the Assessment and Rating of Ataxia (SARA). We found that AI decreased most markedly in both MSA-C and MSA-P, moderately in MJD, and mildly in SCA6 and SCA31. Overall, the AI decrease occurred more rapidly than the SARA score increase. Interestingly, AIs remained normal in purely parkinsonian MSA-P patients (n = 4), but they dropped into the ataxia range when these patients started to show ataxia. The decrease in AI during follow-up (dAI/dt) was significant in patients with SARA scores < 10.5 compared with patients with SARA scores ≥ 10.5, indicating that AI is particularly useful for diagnosing the earlier phase of cerebellar degeneration. We conclude that AI is a useful marker for progressions of cerebellar diseases, and that evaluating the motor learning of patients can be particularly valuable for detecting cerebellar impairment, which is often masked by parkinsonisms and other signs.

Ferdinando Rossi Lecture: the Cerebellar Cognitive Affective Syndrome-Implications and Future Directions.

The notion that the cerebellum is devoted exclusively to motor control has been replaced by a more sophisticated understanding of its role in neurological function, one that includes cognition and emotion. Early clinical reports, as well as physiological and behavioral studies in animal models, raised the possibility of a nonmotor role for the cerebellum. Anatomical studies demonstrate cerebellar connectivity with the distributed neural circuits linked with autonomic, sensorimotor, vestibular, associative and limbic/paralimbic brain areas. Identification of the cerebellar cognitive affective syndrome in adults and children underscored the clinical relevance of the role of the cerebellum in cognition and emotion. It opened new avenues of investigation into higher order deficits that accompany the ataxias and other cerebellar diseases, as well as the contribution of cerebellar dysfunction to neuropsychiatric and neurocognitive disorders. Brain imaging studies demonstrate the complexity of cerebellar functional topography, revealing a double representation of the sensorimotor cerebellum in the anterior lobe and lobule VIII and a triple cognitive representation in the cerebellar posterior lobe, as well as representation in the cerebellum of the intrinsic connectivity networks identified in the cerebral hemispheres. This paradigm shift in thinking about the cerebellum has been advanced by the theories of dysmetria of thought and the universal cerebellar transform, harmonizing the dual anatomic realities of homogeneously repeating cerebellar cortical microcircuitry set against the heterogeneous and topographically arranged cerebellar connections with extracerebellar structures. This new appreciation of the cerebellar incorporation into circuits that subserve cognition and emotion enables deeper understanding and improved care of our patients with cerebellar ataxias and novel cerebellar-based approaches to therapy in neuropsychiatry.

Establishment and characterization of human pluripotent stem cells-derived brain organoids to model cerebellar diseases

The establishment of robust human brain organoids to model cerebellar diseases is essential to study new therapeutic strategies for cerebellum-associated disorders. Machado-Joseph disease (MJD) is a cerebellar hereditary neurodegenerative disease, without therapeutic options able to prevent the disease progression. In the present work, control and MJD induced-pluripotent stem cells were used to establish human brain organoids. These organoids were characterized regarding brain development, cell type composition, and MJD-associated neuropathology markers, to evaluate their value for cerebellar diseases modeling. Our data indicate that the organoids recapitulated, to some extent, aspects of brain development, such as astroglia emerging after neurons and the presence of ventricular-like zones surrounded by glia and neurons that are found only in primate brains. Moreover, the brain organoids presented markers of neural progenitors proliferation, neuronal differentiation, inhibitory and excitatory synapses, and firing neurons. The established brain organoids also exhibited markers of cerebellar neurons progenitors and mature cerebellar neurons. Finally, MJD brain organoids showed higher ventricular-like zone numbers, an indication of lower maturation, and an increased number of ataxin-3-positive aggregates, compared with control organoids. Altogether, our data indicate that the established organoids recapitulate important characteristics of human brain development and exhibit cerebellar features, constituting a resourceful tool for testing therapeutic approaches for cerebellar diseases.

P 6 Visuomotor adaptation is impaired in Essential Tremor

Introduction: Evidence has accumulated to support the theory that the cerebellum is crucially involved in the primary pathophysiology of Essential Tremor (ET). The cerebellum is critical for integration of sensorimotor information to create an internal model of movement using prediction errors. Neurological disorders causing cerebellar injury, such as degenerative cerebellar ataxia or cerebellar stroke, disrupt visuomotor integration and impede error-based learning. We hypothesized that cerebellar dysfunction in ET is also associated with impairment of visuomotor integration and error-based learning. Materials & Methods: To test this hypothesis, mildly to moderately affected ET patients (N=34; mean TETRAS score: 32.15 ± 13.78) and age-matched healthy controls performed a visuomotor adaptation task (Fig. 1A). The task was displayed on a PC monitor and movements were captured using a digital tablet. The experiment was divided into 3 phases (Fig. 1C): a baseline phase (BL), including simple center-to-target movements; an adaptation phase (ADP), in which a 30° visuomotor perturbation was introduced and a de-adaptation phase (DA), in which this perturbation was removed. The angle between the hand path and the center-target path, termed angular error, was calculated to assess visuomotor adaptation (Fig. 1B). Adaptation indices (AI; AI1 = ADP1 – BL2; AI2 = ADP8 – BL2; AI3 = DA1 – ADB8) were evaluated to assess the differences in angular error in each phase of the task (Fig. 2B). Covariates recorded were: clinical characteristics of ET patients, such as disease duration, alcohol responsivity, current medication, clinical measures of tremor and ataxia (as indexed by the TETRAS and SARA score), and basic motor performance as assessed by reaction and movement times. Results: AIs were significantly lower in ET patients compared to controls (Fig. 2A). No differences were found between ET patients and controls at BL or at DA, suggesting that the effects were specific to the adaptation phase. No differences in basic motor performance between groups were evident (all p>0.2), indicating that adaptation deficits in ET were not caused by impaired motor functions. In addition, there was no association between clinical parameters of ET and visuomotor adaptation abilities, suggesting that the reduced ability to adapt the motor response to the visual perturbation was unlikely to result from the tremulous movement. Conclusion: We found that visuomotor adaptation was impaired in ET, specifically in the adaptation phase. These results provide further evidence for linking ET to cerebellar dysfunction. Because the impairment was unrelated to clinical measures of tremor or ataxia and to basic motor performance, cerebellar dysfunction underlying visuomotor impairment in ET may be differentiated from the pathophysiological origin of other cerebellar diseases.

Brain susceptibility imaging provides valuable in vivo insights into cerebellar diseases, but biological interpretations remain elusive.

This scientific commentary relates to: 'Quantitative susceptibility mapping reveals alterations of dentate nuclei in common types of degenerative cerebellar ataxias' by Deistung et al. (https://doi.org/10.1093/braincomms/fcab306).

Cerebellar cognitive affective syndrome due to cerebellar atrophy: case report

Cerebellar atrophy is a rare and challenging disease with few descriptions in the medical literature. Motor impairment is mild, but behavioral and linguistic alterations stand out, in what is known as the cerebellar cognitive affective syndrome secondary to cerebellar atrophy. We report the case of an older woman with early-onset (age 45) signs and symptoms of this syndrome, including impairment of executive functions and visuospatial cognition, personality changes, and language deficits, who was followed at a geriatric medical center for 14 years. Neuropsychological, imaging, and behavioral aspects during this period are discussed in light of scientific evidence. This case report contributes to the scientific literature by describing the progression of the signs and symptoms of cerebellar atrophy over the years, which can help guide medical management and support advice for patients and their families. Keywords: cerebellar ataxia; cerebellar diseases; case reports.

Feasibility of Targeted Delivery of AAV5-GFP into the Cerebellum of Nonhuman Primates Following a Single Convection-Enhanced Delivery Infusion.

In this study, we built upon our previous work to demonstrate the distribution and transport of AAV5-green fluorescent protein (GFP) following a single convection-enhanced delivery infusion into the nonhuman primate cerebellum, with no untoward side effects noted. Dosing under magnetic resonance imaging guidance revealed a sixfold larger volume of distribution compared with the volume of infusion, with no evidence of reflux underscoring the convective properties of the cerebellum and step design of the cannula. Postmortem tissue analysis, 4 weeks post-adeno-associated viral (AAV) delivery, revealed the robust presence of the transgene in situ, with GFP detection in secondary regions not directly targeted by the infusion, denoting distal transport of the vector. Irrespective of tropism, a twofold larger area of transgene expression was found and was corroborated against the presence of contrast on T1-weighted images. Different levels of transduction were detected between animals, which were negatively correlated with the level of antibody titer against the GFP construct, whereby the higher the antibody titer, the lower the level of transgene expression. These findings support the use of the posterior fossa as a potential target site for direct delivery of gene-based therapeutics for cerebellar diseases.

Structural Analysis and Spatiotemporal Expression of Atxn1 Genes in Zebrafish Embryos and Larvae.

Zebrafish have come into focus to model cerebellar diseases such as spinocerebellar ataxias (SCAs), which is caused by an expansion of translated CAG repeats in several unrelated genes. In spinocerebellar ataxia type 1 (SCA1), gain-of-function in the mutant ATXN1 contributes to SCA1’s neuropathy. Human ATXN1 and its paralog ATXN1L are chromatin-binding factors, act as transcriptional repressors, and have similar expression patterns. However, little is known about atxn1 genes in zebrafish. Recently, two family members, atxn1a and atxn1b, were identified as duplicate orthologs of ATXN1, as was atxn1l, the ortholog of ATXN1L. In this study, we analyzed the phylogenetic relationship of the atxn1 family members in zebrafish, compared their genetic structures, and verified the predicted transcripts by both RT-PCR and whole-mount in situ hybridization. All three genes, atxn1a, atxn1b, and atxn1l, show overlapping, but also distinct, expression domains during embryonic and larval development. While atxn1a and atxn1l display similar spatiotemporal embryonic expression, atxn1b expression is initiated during the onset of brain development and is predominantly expressed in the cerebellum throughout zebrafish development. These results provide new insights into atxn1 genes and their expression patterns in zebrafish during embryonic and late-larval development and may contribute importantly to future experiments in disease modeling of SCAs.

Quantification of volumetric morphometry and optical property in the cortex of human cerebellum at micrometer resolution

The surface of the human cerebellar cortex is much more tightly folded than the cerebral cortex. Volumetric analysis of cerebellar morphometry in magnetic resonance imaging studies suffers from insufficient resolution, and therefore has had limited impact on disease assessment. Automatic serial polarization-sensitive optical coherence tomography (as-PSOCT) is an emerging technique that offers the advantages of microscopic resolution and volumetric reconstruction of large-scale samples. In this study, we reconstructed multiple cubic centimeters of ex vivo human cerebellum tissue using as-PSOCT. The morphometric and optical properties of the cerebellar cortex across five subjects were quantified. While the molecular and granular layers exhibited similar mean thickness in the five subjects, the thickness varied greatly in the granular layer within subjects. Layer-specific optical property remained homogenous within individual subjects but showed higher cross-subject variability than layer thickness. High-resolution volumetric morphometry and optical property maps of human cerebellar cortex revealed by as-PSOCT have great potential to advance our understanding of cerebellar function and diseases.

Neuroimaging of Pediatric Cerebellum in Inherited Neurodegenerative Diseases

In the study of cerebellar degenerative diseases, morphologic imaging (computed tomography, CT and magnetic resonance imaging, MRI) is the most common examination. From the clinical and genetic point of view, cerebellar degenerative diseases include heterogeneous conditions in which MRI may show isolated cerebellar atrophy or cerebellar atrophy associated with other cerebellar or supratentorial abnormalities. Neuroradiological progression is often observed. In congenital disorders of glycosylation (CDG), for example, MRI may be normal, may demonstrate mild cerebellar atrophy or, in the advanced stages of the disease, marked atrophy of the cerebellar hemispheres and vermis associated with the abnormal signal intensity of the cerebellar cortex and white matter and brainstem hypotrophy. In spinal cerebellar ataxias (SCAs), very rare in the pediatric population, MRI may demonstrate isolated cerebellar atrophy or cerebellar and brainstem atrophy. MRI shows characteristic findings in other diseases, strongly suggesting a distinct disorder, such as neuroaxonal dystrophy, ARSACS, ataxia-telangiectasia, or precise mitochondrial diseases. An example of neurodegenerative disorder with prenatal onset is pontocerebellar hypoplasia (PCH). PCH represents a group of neurodegenerative disorders characterized by microcephaly, early cerebellar hypoplasia, and variable atrophy of the cerebellum and ventral pons, genetically divided into several subtypes. Cerebellar hypoplasia visible on MRI is often the first sign that suggests the clinical diagnosis. In most cases, the PCH subtype may demonstrate a characteristic pattern distinguishable at MRI. Selective involvement of the cerebellum, sometimes accompanied by brainstem or supratentorial abnormalities in different combinations, may help restrict the differential diagnosis and may address the specific molecular screening.

Cerebellum and its pathologies

Thanks to the work of morphologists and physiologists, on the one hand, and of clinicians, on the other, it seems possible at present to provide a rigorous scientific basis for the study of one of the most difficult and dark chapters of neurology - cerebellar diseases

A narrative review on non-invasive stimulation of the cerebellum in neurological diseases.

The cerebellum plays an important role in motor, cognitive, and affective functions owing to its dense interconnections with basal ganglia and cerebral cortex. This review aimed at summarizing the non-invasive cerebellar stimulation (NICS) approaches used to modulate cerebellar output and treat cerebellar dysfunction in the motor domain. The utility of NICS in the treatment of cerebellar and non-cerebellar neurological diseases (including Parkinson's disease, dementia, cerebellar ataxia, and stroke) is discussed. NICS induces meaningful clinical effects from repeated sessions alone in both cerebellar and non-cerebellar diseases. However, there are no conclusive data on this issue and several concerns need to be still addressed before NICS could be considered a valuable, standard therapeutic tool. Even though some challenges must be overcome to adopt NICS in a wider clinical setting, this tool might become a useful strategy to help patients with lesions in the cerebellum and cerebral areas that are connected with the cerebellum whether one could enhance cerebellar activity with the intention of facilitating the cerebellum and the entire, related network, rather than attempting to facilitate a partially damaged cortical region or inhibiting the homologs' contralateral area. The different outcome of each approach would depend on the residual functional reserve of the cerebellum, which is confirmed as a critical element to be probed preliminary in order to define the best patient-tailored NICS.

The cerebellar cognitive affective syndrome scale reveals early neuropsychological deficits in SCA3 patients

BackgroundThe cerebellar cognitive affective syndrome scale (CCAS-S) was recently developed to detect specific neuropsychological deficits in patients with cerebellar diseases in an expedited manner.ObjectivesTo evaluate the discriminative ability of the CCAS-S in an etiologically homogeneous cohort of spinocerebellar ataxia type 3 (SCA3) patients and to examine relationships between cognitive deficits and motor symptom severity.MethodsThe CCAS-S was administered to twenty mildly to moderately affected SCA3 patients and eighteen healthy controls matched for age, sex, and educational level. Disease severity was measured by the Scale for the Assessment and Rating of Ataxia (SARA), Inventory of Non-Ataxia Signs (INAS), 8 m walk test, nine-hole peg test (9HPT), and Patient Health Questionnaire-9 (PHQ-9).ResultsSCA3 patients had a lower total CCAS-S score (p < 0.001) and higher number of failed tests (p = 0.006) than healthy controls. Patients displayed impairments in semantic fluency, phonemic fluency, category switching, cube drawing, and affect regulation. Total CCAS-S score showed high discriminative ability (area under the curve [AUC]: 0.96) and was associated with disease duration, SARA score, walking speed, and dominant hand 9HPT performance. No correlations were observed with INAS count, repeat length, and PHQ-9 score. Discriminative capacity of the number of failed tests was moderate (AUC: 0.76).ConclusionEssentially all SCA3 patients exhibited some form of cognitive impairment. The CCAS-S differentiates SCA3 patients from healthy controls, detects neuropsychological deficits early in the disease course, and correlates with relevant ataxia severity measures.

Chronic optogenetic stimulation of Bergman glia leads to dysfunction of EAAT1 and Purkinje cell death, mimicking the events caused by expression of pathogenic ataxin-1

Bergmann glia (BG) are highly specialized radial astrocytes of the cerebellar cortex, which play a key role in the uptake of synaptic glutamate via the excitatory amino acid transporter EAAT1. Multiple lines of evidence suggest that in cerebellar neurodegenerative diseases reactive BG has a negative impact on neuronal function and survival through compromised EAAT activity. A family of such diseases are those caused by expansion of CAG repeats in genes of the ataxin family, resulting in spinocerebellar ataxias (SCA).We investigated the contribution of BG to the pathogenesis of cerebellar neurodegeneration in a model of SCA1, which was induced by expression of a polyglutamine mutant of ataxin-1 (ATXN1[Q85]) in BG specifically. We compared the outcomes with a novel model where we triggered excitotoxicity by a chronic optogenetic activation of BG with channelrhodopsin-2 (ChR2). In both cases we detected evidence of reduced glutamate uptake manifested by prolongation of excitatory postsynaptic currents in Purkinje cells which is consistent with documented reduction of expression and/or function of EAAT1. In both models we detected astroglyosis and Purkinje cells atrophy. Finally, the same pattern was detected in a knock-in mouse which expresses a polyglutamine mutant ataxin-1 ATXN1[Q154] in a non-cell-selective manner.Our results suggest that ATXN1[Q85] and ChR2-induced insult targeted to BG closely mimics SCA1 pathology, where excessive glutamate signaling appears to be a common feature likely being an important contributor to cerebellar neurodegeneration.