Biology subjects

Mathews, P. J.

Publications and source records attributed to Mathews, P. J..

3 recordsLinked to original sources

bioRxiv2025

Convergent and Divergent Cerebellar Alterations in 22q11.2 Copy Number Variants

BackgroundIndividuals with copy number variants (CNVs) at 22q11.2 are at elevated risk for neurodevelopmental and psychiatric disorders, including autism spectrum disorder and intellectual disability. For psychosis, effects diverge, with 22q11.2 deletion (22qDel) conferring one of the highest known risks for schizophrenia, while duplication (22qDup) may be protective. Prior investigations of neurobiological mechanisms in 22q11.2 CNVs have predominantly focused on the cerebrum, whereas the cerebellum--a region increasingly recognized for its contributions to cognitive, affective, and social processes--remains underexplored and represents a promising target for investigation. Although alterations in cerebellar structure have been reported in 22qDel, they remain largely unexplored in 22qDup. This study provides the first characterization of regional cerebellar volumes in 22qDup and the first direct comparison of cerebellar structure across 22q11.2 CNVs, offering a unique opportunity to identify shared and distinct neurobiological mechanisms with implications for understanding cerebellar contributions to brain-behavior relationships in CNV carriers. MethodsWe analyzed 514 longitudinally collected structural Magnetic Resonance Imaging (MRI) scans of 111 individuals with 22qDel, 37 individuals with 22qDup, and 167 typically developing (TD) controls. Total and regional cerebellar volumes were quantified using ACAPULCO, a deep-learning-based parcellation method that segments the cerebellum into 28 subregions. Group differences in cerebellar volumes, as well as their associations with cognition, autism-related traits, and psychosis-risk symptoms, were examined using linear mixed-effects models. False discovery rate (FDR) correction was applied to control for multiple comparisons where appropriate. ResultsIn relation to TD controls, cerebellar volumes were broadly reduced in 22qDel, whereas cerebellar alterations in 22qDup were more modest and variable. Regional analyses revealed both linear (22qDel < TD < 22qDup) and nonlinear (22qDel {approx} 22qDup < TD; 22qDel < 22qDup < TD) gene-dosage patterns, though not all reached significance. Vermis VII was significantly reduced in both CNVs but showed no relationship to behavioral differences. In contrast, reduction of Right Lobule VIIIA was associated with greater social impairment in 22qDup. Unlike TD controls, this region was not associated with IQ in 22qDup, suggesting CNV-specific alterations in cerebellar-behavior relationships. ConclusionThese findings indicate that reciprocal CNVs at the 22q11.2 locus both affect cerebellar structure, yet their functional consequences diverge, suggesting overlapping but distinct pathways to clinical risk. They underscore the cerebellums multifaceted role in neurodevelopment and highlight the need for studies examining broader cognitive and socio-affective domains, as well as cerebellar-cortical connectivity, to clarify links to clinical outcomes.

neuroscience↗

bioRxiv2023

Correlated signatures of social behavior in cerebellum and anterior cingulate cortex

The cerebellum has been implicated in the regulation of social behavior. Its influence is thought to arise from communication, via the thalamus, to forebrain regions integral in the expression of social interactions, including the anterior cingulate cortex (ACC). However, the signals encoded or the nature of the communication between the cerebellum and these brain regions is poorly understood. Here, we describe an approach that overcomes technical challenges in exploring the coordination of distant brain regions at high temporal and spatial resolution during social behavior. We developed the E-Scope, an electrophysiology-integrated miniature microscope, to synchronously measure extracellular electrical activity in the cerebellum along with calcium imaging of the ACC. This single coaxial cable device combined these data streams to provide a powerful tool to monitor the activity of distant brain regions in freely behaving animals. During social behavior, we recorded the spike timing of multiple single units in cerebellar right Crus I (RCrus I) Purkinje cells (PCs) or dentate nucleus (DN) neurons while synchronously imaging calcium transients in contralateral ACC neurons. We found that during social interactions a significant subpopulation of cerebellar PCs were robustly inhibited, while most modulated neurons in the DN were activated, and their activity was correlated with positively modulated ACC neurons. These distinctions largely disappeared when only non-social epochs were analyzed suggesting that cerebellar-cortical interactions were behaviorally specific. Our work provides new insights into the complexity of cerebellar activation and co-modulation of the ACC during social behavior and a valuable open-source tool for simultaneous, multimodal recordings in freely behaving mice.

neuroscience↗

bioRxiv2020

A novel, ataxic mouse model of Ataxia Telangiectasia caused by a clinically relevant nonsense mutation

Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated (ATM) and Aprataxin (APTX), respectively. Our mechanistic understanding and therapeutic repertoire for treating these disorders is severely lacking, in large part due to the failure of prior animal models with similar null mutations to recapitulate the characteristic loss of motor coordination (i.e., ataxia) and associated cerebellar defects. By increasing genotoxic stress through the insertion of null mutations in both the Atm (nonsense) and Aptx (knockout) genes in the same animal, we have generated a novel mouse model that for the first time develops a progressively severe ataxic phenotype associated with atrophy of the cerebellar molecular layer. We find biophysical properties of cerebellar Purkinje neurons are significantly perturbed (e.g., reduced membrane capacitance, lower action potential thresholds, etc.), while properties of synaptic inputs remain largely unchanged. These perturbations significantly alter Purkinje neuron neural activity, including a progressive reduction in spontaneous action potential firing frequency that correlates with both cerebellar atrophy and ataxia over the animals first year of life. Double mutant mice also exhibit a high predisposition to developing cancer (thymomas) and immune abnormalities (impaired early thymocyte development and T-cell maturation), symptoms characteristic of A-T. Lastly, by inserting a clinically relevant nonsense-type null mutation in Atm, we demonstrate that Small Molecule Read-Through (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic.

neuroscience↗