Biology subjects

van der Heijden, M. E.

Publications and source records attributed to van der Heijden, M. E..

9 recordsLinked to original sources

bioRxiv2026

Cerebellar mitochondrial dysfunction coincides with structural and behavioral abnormalities in 3q29Del mice

3q29 deletion (3q29Del) is a genetic risk variant for autism spectrum disorder and schizophrenia that often results in developmental delays, cognitive disability, and impaired fine motor function. People with 3q29Del have reduced cerebellar volume, which correlates with symptom severity, and many 3q29Del-associated phenotypes also commonly occur after cerebellar injury or dysfunction. However, it is unknown whether the existing 3q29Del mouse model recapitulates the cerebellar dysfunction observed in humans. To characterize cerebellar phenotypes and uncover pathological differences in the 3q29Del mouse model, we investigated cerebellar structure, motor and vocal behaviors, protein expression, and mitochondrial function. We found uniformly reduced cerebellar volume in 3q29Del mice. Behavioral assays revealed vocal impairments in 3q29Del pups, fine motor impairments in adult mice, and reduced social mating calls in adult male mice. Proteomic analysis revealed enrichment of synaptic and mitochondrial proteins among the differentially expressed proteins in 3q29Del cerebellum tissue. Furthermore, mitochondria from 3q29Del mouse cerebellum displayed reduced oxygen flux and increased electron leak. These results recapitulate many human 3q29Del phenotypes in the 3q29Del mouse model and indicate mitochondrial dysfunction as a potential driver of 3q29Del pathology. Our findings also point to cerebellar involvement in 3q29Del phenotypes and provide a foundation for further research on cerebellar development in 3q29Del.

neuroscience↗

bioRxiv2026

Competitive Olivocerebellar Input Selection Promotes Resilient Circuit Formation

Many neural circuits undergo competitive input selection, a process in which supernumerary connections compete for innervation territory on target cells. This process can create atypical circuits when functional inputs are favored over compromised ones. Yet, it is often unclear whether such atypical circuits are maladaptive or promote functional resilience. We investigated this using the olivocerebellar climbing fiber circuit, where multiple inputs compete to mono-innervate Purkinje cells. We found that eliminating neurotransmission from [~]50% of olivocerebellar neurons reduced climbing fibers competitiveness during input selection and decreased survival of parental inferior olive neurons. Conversely, functional climbing fibers expanded their innervation territory. Despite these atypical circuits, climbing-fiber-dependent motor control was only minimally affected and social behaviors were fully preserved. These results demonstrate that neurotransmission-dependent competition promotes resilient circuits formation, maintaining complex behaviors even when a large proportion of inputs to the cerebellum are developmentally compromised.

neuroscience↗

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↗

bioRxiv2023

Neural spike signatures determine the behavioral presentation of cerebellar disease

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.

neuroscience↗

bioRxiv2022

Influence of data sampling methods on the representation of neural spiking activity in vivo

In vivo single-unit recordings distinguish the basal spiking properties of neurons in different experimental settings and disease states. Here, we examined over 300 spike trains recorded from Purkinje cells and cerebellar nuclei neurons to test whether data sampling approaches influence the extraction of rich descriptors of firing properties. Our analyses included neurons recorded in awake and anesthetized control mice, as well as disease models of ataxia, dystonia, and tremor. We find that recording duration circumscribes overall representations of firing rate and pattern. Notably, shorter recording durations skew estimates for global firing rate variability towards lower values. We also find that only some populations of neurons in the same mouse are more similar to each other than to neurons recorded in different mice. These data reveal that recording duration and approach are primary considerations when interpreting task-independent single-neuron firing properties. If not accounted for, group differences may be concealed or exaggerated.

neuroscience↗

bioRxiv2020

Maturation of Purkinje cell firing properties relies on granule cell neurogenesis

Preterm infants that suffer cerebellar insults often develop motor disorders and cognitive difficulty. Granule cells are especially vulnerable, and they likely instigate disease by impairing the function of Purkinje cells. Here, we use regional genetic manipulations and in vivo electrophysiology to test whether granule cells help establish the firing properties of Purkinje cells during postnatal mouse development. We generated mice that lack granule cell neurogenesis and tracked the structural and functional consequences on Purkinje cells in these agranular pups. We reveal that Purkinje cells fail to acquire their typical connectivity and morphology, and the formation of characteristic Purkinje cell firing patterns is delayed by one week. We also show that the agranular pups have impaired motor behaviors and vocal skills. These data argue that granule cell neurogenesis sets the maturation time window for Purkinje cell function and refines cerebellar-dependent behaviors.

neuroscience↗

bioRxiv2019

Cerebellar Purkinje cell microcircuits are essential for tremor

Tremor is currently ranked as the most common movement disorder. The brain regions and neural signals that initiate the debilitating shakiness of different body parts remain unclear. Here, we found that genetically silencing cerebellar Purkinje cell activity blocked tremor in mice that were given the tremorgenic drug harmaline. We show in awake behaving mice that the onset of tremor is coincident with rhythmic Purkinje cell firing, which alters the output of their target cerebellar nuclei cells. We mimic the tremorgenic action of the drug with optogenetics and present evidence that highly patterned Purkinje cell activity drives a powerful tremor in otherwise normal mice. Modulating the altered activity with deep brain stimulation directed to the Purkinje cell output in the cerebellar nuclei reduced tremor in freely moving mice. Together, the data implicate Purkinje cell connectivity as a neural substrate for tremor and a gateway for signals that mediate the disease.

neuroscience↗

bioRxiv2019

Partial loss of CFIm25 causes aberrant alternative polyadenylation and learning deficits

We previously showed that NUDT21-spanning copy-number variations (CNVs) are associated with intellectual disability (Gennarino et al., 2015). However, the patients CNVs also included other genes. To determine if reduced NUDT21 function alone can cause disease, we generated Nudt21+/- mice to mimic the human state of decreased expression. We found that although these mice have 50% reduced Nudt21 mRNA, they only have 30% less of its cognate protein, CFIm25. Despite this partial protein-level compensation, the Nudt21+/- mice have learning deficits and cortical hyperexcitability. Further, to determine the molecular mechanism driving neural dysfunction, we partially inhibited NUDT21 in human stem cell-derived neurons to reduce CFIm25 by 30%. This reduction in CFIm25 was sufficient to induce misregulated alternative polyadenylation (APA) and protein levels in hundreds of genes, dozens of which cause intellectual disability when mutated. Altogether, these results indicate that disruption of NUDT21-regulated APA events in the brain can cause intellectual disability.

genomics↗