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Synaptic Remodeling in Alzheimer’s Disease Alters the Input-Output Properties of Pyramidal Neurons
No full textAlzheimer\u27s disease (AD), the most common form of dementia, is marked by progressive declines in cognitive function and is associated with the gradual loss of synaptic connectivity within neuronal circuits. The core function performed by neurons is the transformation of synaptic input to the dendrites into action potentials in the axon. Precisely how the loss of connectivity in AD affects these computations is poorly understood. Here, I use a computational model of a reconstructed hippocampal CA1 pyramidal cell to uncover how synapse loss impacts computations. The model, developed in the NEURON environment, simulates excitatory synapses to drive dendritic and somatic excitatory postsynaptic potentials. The model was adapted to reflect two changes found in AD mouse models: first, the widespread loss of synapses across the dendritic arbor, and second, the more focal loss of synapses at amyloid plaques adjacent to portions of dendrites. Through this approach, I show that spine loss causes dendritic branches to be more excitable due to increased input resistance, and that plaque-induced shifts in the spatial distribution of synapses can lead to both hypo- and hyperexcitable states within a single dendritic branch. Understanding how dendritic spine loss impacts cell excitability may prove valuable in directly linking how changes at the synapse alter the computational properties of neurons, possibly informing new strategies to address synaptic disconnection in AD progression
Quantifying genetic mapping power in a Diversity Outbred mouse population
No full textGenetic mapping is a powerful tool that can be used to elucidate the genetic basis of complex traits, including disease. Locating loci across the genome that contain variants which drive quantitative traits can provide a link between genetic variation and phenotypic variation, informing improved targeted therapeutics. A class of variants known as expression quantitative trait loci (eQTLs) are especially important to understanding the genetic basis of disease, but eQTL mapping studies are often limited by low statistical power. Here, we analyze Diversity Outbred (DO) mouse datasets to empirically evaluate how sample size and eQTL effect size impact power and false discovery rate in eQTL mapping. We demonstrate how decreasing sample size reduces detection power and mapping precision, a result that is accentuated in eQTLs with modest effect sizes. We find that the power to detect distal eQTLs is lost more rapidly with reduced sample size than the power to detect local eQTLs, introducing potential biases in biological interpretation. We quantify these effects by constructing power and false discovery rate curves, and we fit two generalized additive models to these curves which form the basis of our DO eQTL power calculator. Our results highlight the importance of adequate sample size in eQTL mapping in DO mice and provide an interactive tool to guide researchers in experimental design
Impact of Age and Sex on Bladder Function and Stum Gene Expression in C57BL/6J Mice
No full textBladder dysfunction has an intense emotional and economic impact on both patients and their families. However, it is alarmingly under researched and misunderstood. Currently, there are no genetic targets for bladder function. This study aims to connect bladder function, Stum expression, aging, and sex in C57BL/6J mice.
In a recent study, a gene atlas of the mouse bladder was generated using bulkRNAseq, single-cell RNAseq, single-nucleus RNAseq, and spatial transcriptomics (Visium) (bioRxiv 2021.09.20.461121). Among the novel detrusor smooth muscle (DSM) specific genes identified in this study was Stum. Stum has been found to be key in the function of proprioceptive neurons (Desai et.al., 2014). Similar proprioception cells are present in the bladder and play a role in sensing bladder pressure and therefore urination (Gonzalez et.al., 2014). In previous experiments, our lab has shown that when Stum was knocked-out, male bladder function decreased. This was not reflected in the female population. Further investigation of Stum expression and bladder function, as well as the location of Stum expression in the bladder could uncover novel information about bladder function across age and sex.
Through void spot assay (VSA) it was found that older males had lower bladder function (expressed in higher number of voids) than their younger counterparts (p=0.05), as well as females of the same age (p=0.02). Females maintained bladder function (no significant difference between age groups). RNAscope assay of bladder tissue revealed Stum to be more prevalent in the mucosa in females (p=0.0005), and more prevalent in the muscularis tissue in males (p=0.0003). qPCR analysis that old males had lower Stum expression than females of the same age (p=0.02).
The findings of this study indicate that Stum may be a sex-linked explanation for declining bladder function, and the first genetic target for bladder dysfunction therapy
RareLink: scalable REDCap-based framework for rare disease interoperability linking international registries to FHIR and Phenopackets.
No full textWhile Research Electronic Data Capture (REDCap) is widely adopted in rare disease research, its unconstrained data format often lacks native interoperability with global health standards, limiting secondary use. We developed RareLink, an open-source framework implementing our published ontology-based rare disease common data model. It enables standardised data exchange between REDCap, international registries, and downstream analysis tools by linking Global Alliance for Genomics and Health Phenopackets and Health Level 7 Fast Healthcare Interoperability Resources (FHIR) instances conforming to International Patient Summary and Genomics Reporting profiles. RareLink was developed in three phases across Germany, Canada, South Africa, and Japan for registry and data analysis purposes. We defined a simulated Kabuki syndrome cohort and demonstrated data export to Phenopackets and FHIR. RareLink can enhance the clinical utility of REDCap through its global applicability, supporting equitable rare disease research. Broader adoption and coordination with international entities are thus essential to realise its full potential
Accessible, Realistic Genome Simulation with Selection Using stdpopsim.
No full textSelection is a fundamental evolutionary force that shapes patterns of genetic variation across species. However, simulations incorporating realistic selection along heterogeneous genomes in complex demographic histories are challenging, limiting our ability to benchmark statistical methods aimed at detecting selection and to explore theoretical predictions. stdpopsim is a community-maintained simulation library that already provides an extensive catalog of species-specific population genetic models. Here, we present a major extension to the stdpopsim framework that enables simulation of various modes of selection, including background selection, selective sweeps, and arbitrary distributions of fitness effects (DFE) acting on annotated subsets of the genome (for instance, exons). This extension maintains stdpopsim\u27s core principles of reproducibility and accessibility while adding support for species-specific genomic annotations and published DFE estimates. We demonstrate the utility of this framework by comparing methods for demographic inference, DFE estimation, and selective sweep detection across several species and scenarios. Our results demonstrate the robustness of demographic inference methods to selection on linked sites, reveal the sensitivity of DFE-inference methods to model assumptions, and show how genomic features, like recombination rate and functional sequence density, influence power to detect selective sweeps. This extension to stdpopsim provides a powerful new resource for the population genetics community to explore the interplay between selection and other evolutionary forces in a reproducible, user-friendly framework
Interindividual Genetic Differences Drive Discordance Between Serum Calcidiol and Calcitriol Concentrations in Females.
No full textVitamin D insufficiency (VDI) is primarily determined by serum levels of calcidiol, which serves as a biomarker for the less abundant but most potent bioactive metabolite, calcitriol. However, population studies often show discordance between calcidiol and calcitriol. Here, a genetically diverse population of 7 inbred mouse strains was used to investigate the role of interindividual genetic differences in driving calcidiol-to-calcitriol discordance under vitamin D sufficient (VDS) vs depleted (VDD) conditions. We found high interstrain variability in calcitriol that was discordant with calcidiol under VDS and VDD conditions. However, under VDS conditions, stratification by calcitriol level revealed that strains with serum calcitriol \u3e60 pM (HighC) exhibited the expected positive calcidiol-to-calcitriol association, whereas strains with low calcitriol (\u3c 60 pM, LowC) did not. Thus, discordance under VDS was driven by genetically divergent strains with LowC. Discordance under VDD was not associated with LowC. LowC was not caused by increased calcitriol degradation or by transcriptional dysregulation of canonical vitamin D metabolism enzymes. Instead, LowC strains exhibited low renal expression of Lrp2 (megalin), the primary transporter required for renal calcitriol production. LowC strains also exhibited reduced renal expression of the vitamin D receptor (Vdr) and several target genes, demonstrating impaired vitamin D signaling. These findings reveal novel, naturally occurring genetic determinants of VDI that function by disrupting calcitriol production and signaling in a manner that cannot be predicted by calcidiol levels. Cross-species conservation of this phenomenon would have important implications for clinical management of VDI and related disease risks across genetically diverse populations
The Neuromuscular Junction: A Shared Vulnerability in Aging and Disease.
No full textThe neuromuscular junction (NMJ) is a specialized synapse essential for effective motor neuron-muscle communication and is increasingly recognized as a vulnerable site in aging and neuromuscular disease. While traditionally considered a final common pathway for motor deficits, accumulating evidence demonstrates that NMJ dysfunction is an early and critical driver of disease onset and progression in conditions such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease. This review highlights shared and disease-specific mechanisms contributing to NMJ impairment, including presynaptic, postsynaptic, and perisynaptic Schwann cell defects in these diseases. We also discuss age-related changes at the NMJ, emphasizing its role in sarcopenia and muscle weakness in older adults. Furthermore, we explore emerging molecular drivers of NMJ dysfunction uncovered through studies in congenital myasthenic syndromes, autoimmune disorders, and advanced omics approaches. By integrating insights across diseases and aging, we underscore the potential for shared therapeutic strategies aimed at stabilizing NMJ function. Promising interventions targeting presynaptic neurotransmitter release, postsynaptic excitability, and perisynaptic Schwann cells are discussed as avenues to improve neuromuscular transmission and maintain muscle strength. Finally, we discuss the challenges and opportunities in translating these mechanistic insights into clinical therapies and highlight how novel human neuromuscular organoid models and advanced molecular profiling can bridge this gap. Together, these insights establish the NMJ as a critical, modifiable target for preserving motor function across neuromuscular diseases and aging
Humanized Mouse Models for Type 1 Diabetes.
No full textT cell-mediated autoimmune type 1 diabetes (T1D) is under complex polygenic control in both humans and the NOD mouse model. However, in both species, particular major histocompatibility complex (MHC; designated HLA in humans) haplotypes provide the primary T1D risk factor. Both MHC/HLA class I and II variants interactively contribute to T1D by respectively driving autoreactive CD8 and CD4 T cell responses that cooperatively destroy insulin-producing pancreatic β cells. While NOD mice have provided important insights to the pathogenic basis of T1D, the model has so far provided only a limited means to identify possible clinically translatable disease intervention approaches. This highlights a need to humanize NOD mice in ways that their pathogenic basis of T1D development becomes more similar to that characterizing the disease course in patients. In this review, we discuss the use of CRISPR/Cas9-generated murine-MHC-deficient NOD mice as a platform for introduction of patient-relevant HLA and T cell receptor molecules. These mice provide ever-improving models for development of clinically applicable interventions for T1D and other autoimmune diseases. © 2025 The Author(s) Current Protocols published by Wiley Periodicals LLC