Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.02.23.481672

Structural and functional alterations of neuromuscular synapses in a mouse model of ACTA1 congenital myopathy

Liu, Y.·Lin, W.
View original source ↗Export metadata ↓

Abstract

Mutations in skeletal muscle -actin (Acta1) cause a variety of myopathies. In a mouse model of congenital myopathy, heterozygous Acta1 (H40Y) knock-in (Acta1+/Ki) mice exhibit features of human nemaline myopathy, including premature lethality, severe muscle weakness, reduced mobility, and the presence of nemaline rods in muscle fibers. In this study, we investigated the structure and function of the neuromuscular junction (NMJ) in the Acta1+/Ki mice. We found marked impairments in NMJ structure in the mutant mice, including fragmented endplates and nerve terminals, reduced density of acetylcholine receptors (AChRs) on endplate membranes, reduced nerve occupancy at endplates, and increased numbers of muscle fiber subsynaptic nuclei. We compared the NMJs in three different types of muscles - the extensor digitorum longus (EDL, composed of fast-twitch muscle fibers), soleus (Sol, enriched in slow-twitch fibers) and the triangularis sterni muscle (TS, a mixed fiber type muscle). Among these three types of muscles, EDL was affected to the greatest extent, suggesting that fast-twitch fibers may be most susceptible to NMJ fragmentation in Acta1+/Ki nemaline myopathy. Electrophysiological analysis of mutant NMJs showed a reduced quantal size (reduced mEPP amplitude), increased mEPP frequency, and increased quantal content, but normal EPP amplitude compared to wild type (WT) NMJs. The results suggest that affected synapses may have undergone homeostatic compensation to maintain normal levels of neurotransmitter release. In addition, paired-pulse facilitation was reduced and synaptic depression under repetitive nerve stimulation was enhanced, indicating shortterm synaptic plasticity was compromised in the mutant mice. Key pointsO_LIMice heterozygous for an Acta1 (H40Y) knock-in mutation exhibit clinical features of human nemaline myopathy. We report structural and functional alterations of neuromuscular synapses in these mutant mice. The NMJ impairments include endplate fragmentation, reduced endplate nerve occupancy, and increased numbers of subsynaptic nuclei in muscle fibers. C_LIO_LINeuromuscular synaptic transmission was compromised - demonstrating both increased quantal content and changes in short-term synaptic plasticity. C_LIO_LIIncreases in spontaneous neurotransmitter release and quantal content suggest homeostatic compensation of synapses to maintain normal transmitter release in the mutant NMJs. C_LI

Explore related subjects

neurosciencePreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Liu, Y., Lin, W.. 2022-02-25. Structural and functional alterations of neuromuscular synapses in a mouse model of ACTA1 congenital myopathy. https://doi.org/10.1101/2022.02.23.481672

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations consistently outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗
bioRxiv2026

A nonlinear inhibition pathway underlying cortical responses to tuned holographic optogenetic perturbations

Optogenetics enables causal manipulation of cortical activity. Perturbation responses can be counterintuitive due to network interactions, making theory essential for predicting them. Existing approaches often rely on linear approximations, which fail for many biologically relevant perturbations. Here we develop a nonlinear theory of responses to holographic perturbations in cell-type-specific recurrent networks with structured connectivity. We fit a nonlinear model to mouse V1 data, which shows cotuned-ensemble suppression: perturbing spatially clustered neurons with similar preferred orientations yields markedly stronger short-range suppression than perturbing untuned ensembles. We show that cotuned-ensemble suppression arises from a feature-tuned, nonlinear inhibition pathway implicating somatostatin-positive (SST) interneurons. The theory predicts that cotuned ensembles suppress parvalbumin-positive (PV) neurons but facilitate SST neurons, and links the degree of cotuned-ensemble suppression or facilitation to the variance of the SST response. This framework identifies mechanisms by which nonlinear inhibition sculpts cortical dynamics and establishes a predictive basis for targeted optogenetic interventions.

neuroscience↗
bioRxiv2026

Proteomic signatures of APOE ε4 across human tissues and cell types in Alzheimers disease

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, the underlying molecular mechanisms remain unclear. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimers Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). To characterise APOE {varepsilon}4 molecular effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. The association of APOE {varepsilon}4 with AD neuropathology was also examined. APOE {varepsilon}4 carriers shared a plasma proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this signature discriminated APOE {varepsilon}4 carriers from non-carriers in an independent cohort using CSF proteomics. APOE {varepsilon}4 carriage was associated with higher Braak stages and Consortium to Establish a Registry for Alzheimers Disease (CERAD) score. However, only limited APOE {varepsilon}4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor cross-layer concordance. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE {varepsilon}4-associated changes. APOE {varepsilon}4 is associated with a consistent proteomic signature across plasma and CSF. Its molecular effects in the brain differ across cell types, brain regions and molecular layers. These findings support the need for cell-type-resolved multi-omic studies to elucidate how APOE {varepsilon}4 confers AD risk.

neuroscience↗