Biology subjects

Watt, A. J.

Publications and source records attributed to Watt, A. J..

5 recordsLinked to original sources

bioRxiv2026

Zebrin molecular identity and cerebellar location determine Purkinje cell vulnerability in Christianson syndrome mice

Ataxia is a major characteristic feature in Christianson syndrome, where Purkinje cells in the anterior cerebellar vermis are vulnerable to degeneration while those in the posterior vermis are resilient. Here, we provide a temporal study of changes in Purkinje cell function, cell vulnerability and innervation of cerebellar nuclei in a mouse model of Christianson syndrome. Purkinje cells express certain molecules in a patterned manner across the cerebellum, such as aldolase C/zebrin-II (zebrin). We show that zebrin patterning appears normal before disease onset in Christianson syndrome mice with no apparent cell death, similar to what has been reported in patients. We observe rapid Purkinje cell death in the anterior lobe of Christianson syndrome mice that is exclusive to zebrin-negative Purkinje cells, with zebrin-positive Purkinje cells showing resilience. Intrinsic firing deficits exclusively in the anterior cerebellum are observed at the same time as the first observed cell death in the anterior cerebellum. In contrast, posterior Purkinje cells degenerated later, but zebrin-negative and zebrin-positive cells were equally susceptible to degeneration. Purkinje cells innervation in the cerebellar nuclei was also lost in Christianson syndrome mice in a region-specific manner: neurons in the anterior cerebellar nuclei, with predominantly zebrin-negative Purkinje cells inputs, displayed dramatic loss of Purkinje cells innervation, while neurons in the posterior cerebellar nuclei, innervated by both zebrin-negative and zebrin-positive terminals, showed greater resiliency. Together, our results highlight that cerebellar location and zebrin molecular identity appear important to the vulnerability of Purkinje cells and their innervation in the cerebellar nuclei in Christianson syndrome. HIGHLIGHTSO_LIFirst study showing Purkinje cell intrinsic firing alterations in Christianson syndrome mice. C_LIO_LIZebrin patterning appears normal before disease onset in Christianson syndrome mice. C_LIO_LIPurkinje cell firing deficits and death start at post-natal day 35 only in the anterior cerebellum in a Christianson syndrome mouse model. C_LIO_LIZebrin-negative and zebrin-positive Purkinje cells in the posterior cerebellum are initially resilient but are both equally susceptible to Purkinje cell death at later stages of the disorder. C_LIO_LIZebrin-negative Purkinje cell inputs to the anterior cerebellar nuclei are lost, while zebrin-positive inputs remain. C_LIO_LIThe pattern of Purkinje cell death in Christianson Syndrome is similar to that of many rare ataxias, suggesting a comparable underlying pathophysiology, which could lead to common therapeutic targets. C_LI

neuroscience↗

bioRxiv2024

Human-specific features of cerebellar astrocytes and Purkinje cells: an anatomical comparison with mice and macaques

Little is known about the morphological diversity and distribution of cerebellar astrocytes in the human brain and how or if these features differ from those of cerebellar astrocytes in species used to model human illnesses. To address this, we performed a comparative post-mortem examination of cerebellar astrocytes and Purkinje cells (PCs) in healthy humans, macaques, and mice using microscopy-based techniques. Visualizing with canonical astrocyte markers glial fibrillary acidic protein (GFAP) and aldehyde dehydrogenase-1 family member L1 (ALDH1L1), we mapped astrocytes within a complete cerebellar hemisphere. Astrocytes were observed to be differentially distributed across the cerebellar layers, displayed overall increases in area coverages with evolution, and showed features uniquely hominoid. Stereological quantifications in 3 functionally distinct cerebellar lobules demonstrated opposing trends for the canonical astrocyte markers across species with ALDH1L1+ astrocytes increasing with evolution and GFAP+ astrocytes decreasing. PC analyses revealed that while humans have the lowest PC densities, their cell body sizes were the largest with more ALDH1L1 immunoreactive astrocytes surrounding. Notably, the cognitive lobule crus I displayed the highest ratio of Bergmann glia to PC in all species. These findings align with the growing literature for astrocyte and PC heterogeneity and suggest cerebellar astrocyte and PC divergence both within and across species, possibly indicative of a role for these cells in higher-order cerebellar processing.

neuroscience↗

bioRxiv2023

Endosomal dysfunction contributes to cerebellar deficits in spinocerebellar ataxia type 6

Spinocerebellar ataxia type 6 (SCA6) is a rare disease that is characterized by cerebellar dysfunction. Patients have progressive motor coordination impairment, and postmortem brain tissue reveals degeneration of cerebellar Purkinje cells and a reduced level of cerebellar brain-derived neurotrophic factor (BDNF). However, the pathophysiological changes underlying SCA6 are not fully understood. We carried out RNA sequencing of cerebellar vermis tissue in a mouse model of SCA6, which revealed widespread dysregulation of genes associated with the endo-lysosomal system. Since disruption to endosomes or lysosomes could contribute to cellular deficits, we examined the endo-lysosomal system in SCA6. We identified alterations in multiple endosomal compartments in the Purkinje cells of SCA6 mice. Early endosomes were enlarged, while the size of the late endosome compartment was reduced. We also found evidence for impaired trafficking of cargo to the lysosomes. As the proper functioning of the endo-lysosomal system is crucial for the sorting and trafficking of signaling molecules, we wondered whether these changes could contribute to previously identified deficits in signaling by BDNF and its receptor tropomyosin kinase B (TrkB) in SCA6. Indeed, we found that the enlarged early endosomes in SCA6 mice accumulated both BDNF and TrkB. Furthermore, TrkB recycling to the cell membrane in recycling endosomes was reduced, and the late endosome transport of BDNF for degradation was impaired. Therefore, mis-trafficking due to aberrant endo-lysosomal transport and function could contribute to SCA6 pathophysiology through alterations to BDNF-TrkB signaling, as well as mishandling of other signaling molecules. Deficits in early endosomes and BDNF localization were rescued by chronic administration of a TrkB agonist, 7,8-DHF, that we have previously shown restores motor coordination and cerebellar TrkB expression. The endo-lysosomal system is thus both a novel locus of pathophysiology in SCA6, and a promising therapeutic target.

neuroscience↗

bioRxiv2023

Structured connectivity in the output of the cerebellar cortex

Circuits in the brain are built from connections between neurons, where the spatial organization and functional properties of these connections determines circuit function. In the cerebellum, Purkinje cells transmit information to neurons in the cerebellar nuclei, but how Purkinje cell - nuclear neuron connections are organized remains unclear. Here, we explored the connections between Purkinje cells and cerebellar nuclear neurons using whole-cell electrophysiology and optogenetics to produce spatial connectivity maps of cerebellar cortical output. We observed non-random connectivity between Purkinje cells and their target neurons, with inputs to cerebellar nuclear neurons clustering along cerebellar transverse zones. While many nuclear neurons received inputs from a single zone, a number of different connectivity motifs were observed. Neurons receiving inputs from all four zones were more common than predicted by a random model and showed topographic organization in the nucleus. Finally, we observed that small Purkinje cell inputs were sufficient to pause the output of nuclear neurons, suggesting that widespread Purkinje cell synchrony may not be necessary to influence cerebellar output. These findings reveal cerebellar nuclear neurons as an important locus of multimodal cerebellar integration.

neuroscience↗

bioRxiv2021

Restoration of BDNF-TrkB signaling rescues deficits in a mouse model of SCA6

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease resulting in motor coordination deficits and cerebellar pathology. Expression of brain-derived neurotrophic factor (BDNF) is reduced in several neurodegenerative diseases, including in post-mortem tissue from SCA6 patients. Here, we show that cerebellar BDNF levels are reduced at an early disease stage in a mouse model of SCA6 (SCA684Q/84Q). One month of voluntary exercise was sufficient to elevate BDNF expression, as well as rescue both motor coordination and cerebellar Purkinje cell firing rate deficits. A BDNF mimetic, 7,8-dihydroxyflavone (7,8-DHF) likewise improved motor coordination and reversed Purkinje cell firing rate deficits, suggesting that exercise acts via BDNF-TrkB signaling. Prolonged chronic 7,8-DHF administration rescued ataxia when treatment commenced near disease onset, but was ineffective when treatment was started late. These data suggest that 7,8-DHF, which is orally bioavailable and crosses the blood-brain barrier, is a promising therapeutic for SCA6 and argue for the importance of early intervention for SCA6.

neuroscience↗