Biology subjects

Lyon, A. M.

Publications and source records attributed to Lyon, A. M..

3 recordsLinked to original sources

bioRxiv2025

Modeling Laryngeal Dystonia through Spectral Analyses of Vocalizations in a Dystonia Mouse Model

Laryngeal dystonia is a task-specific, focal dystonia that disrupts vocal-motor control and significantly alters quality of life through impaired communication. Despite its early onset in many hereditary dystonias, effective treatments remain limited, in part due to the lack of a preclinical model that captures its circuit-level pathophysiology. Our experiment evaluates ultrasonic vocalizations (USVs) in Ptf1aCre/+;Vglut2fl/fl mice, a cerebellum-specific generalized dystonia model, to assess translational relevance for laryngeal dystonia. At postnatal day 9, mutant mice demonstrated statistically significant reductions in total USV count, relative count of complex calls, and key spectral parameters-- especially frequency modulation and power--mirroring phonatory abnormalities seen in human patients. Cluster analyses further revealed impaired vocal burst initiation, suggesting disrupted cerebellar coordination of temporal vocal-motor output. These findings support the models construct and face validity for cerebellar contributions to disordered phonation. By revealing these potential translational biomarkers, our study establishes a foundational platform for future mechanistic and interventional research in laryngeal dystonia. SUMMARY STATEMENTWe demonstrate that a cerebellar general dystonia mouse model recapitulates vocal-motor deficits seen in laryngeal dystonia, providing a foundational platform for mechanistic studies and translational therapeutic discovery.

neuroscience↗

bioRxiv2025

Purkinje Cell spike patterns do not correlate with nuclei cell spike patterns in mouse models for cerebellar disease

Cerebellar dysfunction causes various movement disorders, including ataxia, dystonia, and tremor. Previous work demonstrated that spike patterns in cerebellar nuclei neurons were distinct between different movement disorder mouse models. However, often these changes arise from neural dysfunction in the cerebellar cortex, through misfiring, miswiring, or degenerating Purkinje cells. Even though Purkinje cells form the sole output from the cerebellar cortex, their information is relayed to other regions of the motor network via cerebellar nuclei cells. Purkinje cells make GABAergic synapses onto cerebellar nuclei cells, and it is often assumed that changes in Purkinje cell spike patterns result in inverse changes in nuclei cell spike patterns. Here, we test this hypothesis by answering the question of whether a reliable relationship between Purkinje cell and nuclei cell spike patterns exists. Single-cell, in vivo electrophysiology recordings of both cell types from six mouse models for cerebellar movement disorders were analyzed according to parameters relating to spike rate and irregularity. We investigated whether Purkinje cell spike patterns correlated with nuclei cell spike patterns. We found that some parameters for firing irregularity were positively correlated between Purkinje and nuclei cells but no - and particularly no inverse - relationship was observed between Purkinje and nuclei cell spike rate. Overall, this study begins to illuminate that the relationship between Purkinje cells and nuclei cell spike activity in a disease state is more complex and unpredictable. The data suggest Purkinje cell spike activity changes cannot accurately predict nuclei cell changes, which ultimately drive cerebellar disease states. Our findings underscore the importance of studying cerebellar nuclei cell function in cerebellar disease, as lack of changes in Purkinje cell firing patterns can mask disease-causing firing patterns in these cerebellar output cells.

neuroscience↗

bioRxiv2024

Cryo-EM Structure of Phospholipase Cϵ Defines N-terminal Domains and their Roles in Activity

Phospholipase C{varepsilon} (PLC{varepsilon}) increases intracellular Ca2+ and protein kinase C (PKC) activity in the cardiovascular system in response to stimulation of G protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). The ability of PLC{varepsilon} to respond to these diverse inputs is due, in part, to multiple, conformationally dynamic regulatory domains. However, this heterogeneity has also limited structural studies of the lipase to either individual domains or its catalytic core. Here, we report the 3.9 [A] reconstruction of the largest fragment of PLC{varepsilon} to date in complex with an antigen binding fragment (Fab). The structure reveals that PLC{varepsilon} contains a pleckstrin homology (PH) domain and four tandem EF hands, including subfamily-specific insertions and intramolecular interactions with the catalytic core. The structure, together with a model of the holoenzyme, suggest that part of the N-terminus and PH domain form a continuous surface that could engage cytoplasmic leaflets of the plasma and perinuclear membranes, contributing to activity. Functional characterization of this surface confirm it is critical for maximum basal and G protein-stimulated activities. This study provides new insights into the autoinhibited, basal conformation of PLC{varepsilon} and the first mechanistic insights into how it engages cellular membranes for activity.

biochemistry↗