Neurobiology of Disease最新文献

{"title":"Microstructural changes in the caudate nucleus and hippocampus and their association with cognitive function in cerebral small vessel disease: A quantitative susceptibility mapping study","authors":"Yiwen Chen ,&nbsp;Meng Li ,&nbsp;Jing Li ,&nbsp;Yian Gao ,&nbsp;Chaofan Sui ,&nbsp;Na Wang ,&nbsp;Xinyue Zhang ,&nbsp;Yuanyuan Wang ,&nbsp;Zhenyu Cheng ,&nbsp;Pengcheng Liang ,&nbsp;Lingfei Guo ,&nbsp;Qihao Zhang ,&nbsp;Changhu Liang","doi":"10.1016/j.nbd.2025.106964","DOIUrl":"10.1016/j.nbd.2025.106964","url":null,"abstract":"<div><h3>Background</h3><div>Cerebral small vessel disease (CSVD) is associated with microstructural changes in subcortical gray matter linked to cognitive function. These changes may vary across different subregions. The aim of our study was to explore microstructural alterations in subcortical gray matter subregions associated with cognition in CSVD patients using magnetic resonance (MR) quantitative susceptibility mapping (QSM).</div></div><div><h3>Methods</h3><div>A total of 295 participants were included in the study, consisting of 112 healthy controls (HC), 85 with mild CSVD, and 98 with severe CSVD. All participants underwent MRI scans and cognitive function assessments. QSM images were segmented into 32 subcortical gray matter regions. Differences in susceptibility values across the three groups and their relationships with clinical and cognitive function were analyzed.</div></div><div><h3>Results</h3><div>After adjusting for potential confounders, the susceptibility values of the posterior part of the right hippocampus (pHIPr) (β = 1.209, <em>P</em> = 0.030) and the posterior part of the right caudate (pCAUr) (β = 4.373, <em>P</em> = 0.005) were positively correlated with CSVD severity. In the CSVD cohort, the mean susceptibility values of pCAUr were significantly associated with various cognitive functions. Furthermore, a simple mediation model demonstrated that the mean susceptibility value of pCAUr mediated the relationship between CSVD burden and SCWT score (indirect effect = 2.309, 95 % CI = 0.450–4.986, Pm = 21.5 %).</div></div><div><h3>Conclusion</h3><div>Our study revealed a relationship between microstructural changes of subcortical gray matter in CSVD patients and cognitive function and highlighted the potential of QSM in detecting brain microstructural alterations associated with cognition.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106964"},"PeriodicalIF":5.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144117066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Network models incorporating chloride dynamics predict optimal strategies for terminating status epilepticus","authors":"Christopher B. Currin ,&nbsp;Richard J. Burman ,&nbsp;Tommaso Fedele ,&nbsp;Georgia Ramantani ,&nbsp;Richard E. Rosch ,&nbsp;Henning Sprekeler ,&nbsp;Joseph V. Raimondo","doi":"10.1016/j.nbd.2025.106966","DOIUrl":"10.1016/j.nbd.2025.106966","url":null,"abstract":"<div><div>Status epilepticus (SE), seizures lasting beyond five minutes, is a medical emergency commonly treated with benzodiazepines which enhance GABA_A receptor (GABA_AR) conductance. Despite widespread use, benzodiazepines fail in over one-third of patients, potentially due to seizure-induced disruption of neuronal chloride (Cl⁻) homeostasis. Understanding these changes at a network level is crucial for improving clinical translation. Here, we address this using a large-scale spiking neural network model incorporating Cl⁻ dynamics, informed by clinical EEG and experimental slice recordings. Our simulations confirm that the GABA_AR reversal potential (E_GABA) dictates the pro- or anti-seizure effect of GABA_AR conductance modulation, with high E_GABA rendering benzodiazepines ineffective or excitatory. We show SE-like activity and E_GABA depend non-linearly on Cl⁻ extrusion efficacy and GABA_AR conductance. Critically, cell-type specific manipulations reveal that pyramidal cell, not interneuron, Cl⁻ extrusion predominantly determines the severity of SE activity and the response to simulated benzodiazepines. Leveraging these mechanistic insights, we develop a predictive framework mapping network states to Cl⁻ extrusion capacity and GABAergic load, yielding a proposed decision-making strategy to guide therapeutic interventions based on initial treatment response. This work identifies pyramidal cell Cl⁻ handling as a key therapeutic target and demonstrates the utility of biophysically detailed network models for optimising SE treatment protocols.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106966"},"PeriodicalIF":5.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144128347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of presenilin mutations that have sufficient gamma-secretase proteolytic activity to mediate Notch signaling but disrupt organelle and neuronal health","authors":"Zahra Ashkavand ,&nbsp;Kerry C. Ryan ,&nbsp;Jocelyn T. Laboy,&nbsp;Ritika Patel,&nbsp;Brian Geller,&nbsp;Kenneth R. Norman","doi":"10.1016/j.nbd.2025.106961","DOIUrl":"10.1016/j.nbd.2025.106961","url":null,"abstract":"<div><div>Mutations that cause familial Alzheimer's disease (AD) are predominantly found in the presenilin (PSEN) encoding genes <em>PSEN1</em> and <em>PSEN2</em>. While the association of PSEN mutations with familial AD have been known for over 20 years, the mechanism underlying the impact these mutations have on disease is not fully understood. PSENs are phylogenetically conserved proteins that are found in diverse multicellular organisms ranging from plants to humans. PSENs form the proteolytic core of gamma-secretase that is required for cleaving type I transmembrane proteins, such as Notch receptors and the amyloid precursor protein. Importantly, familial AD-associated PSEN mutations are broadly distributed and do not clearly define a specific PSEN function essential for neuronal fitness. Here, using <em>C. elegans</em> as a model organism to study the in vivo functions of PSENs, we confirm that <em>C. elegans</em> PSEN plays a pivotal role in gamma-secretase proteolytic activity as well as maintaining neuronal and organelle health. Notably, we demonstrate that these two functions can be genetically uncoupled. Our research identifies several conserved familial AD-like missense mutations in the endogenous <em>sel-12</em> gene, which encodes <em>C. elegans</em> PSEN. These mutations preserve sufficient gamma-secretase proteolytic activity to mediate Notch signaling but abolish PSEN's role in supporting neuronal and organelle health. Furthermore, we provide evidence that these familial AD-like missense mutations disrupt mitochondrial calcium regulation, ultimately leading to neuronal dysfunction. These results indicate that <em>C. elegans</em> PSEN plays at least two independent roles: one that mediates gamma-secretase proteolytic activity and another that mediates organelle and neuronal health.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106961"},"PeriodicalIF":5.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144107559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic and glucose metabolism of connectome dynamics variability in temporal lobe epilepsy revealed by simultaneous PET-fMRI","authors":"Jie Hu ,&nbsp;Bixiao Cui ,&nbsp;Zhenming Wang ,&nbsp;Jingjuan Wang ,&nbsp;Xiaoyin Xu ,&nbsp;Jie Lu","doi":"10.1016/j.nbd.2025.106967","DOIUrl":"10.1016/j.nbd.2025.106967","url":null,"abstract":"<div><div>Temporal lobe epilepsy (TLE) is associated to genetic predisposition, metabolic abnormalities, and disruptions in brain connectivity. However, the relationships between genetic factors, metabolic processes, and brain network dynamics are not yet fully understood. Simultaneous positron emission tomography and function magnetic resonance imaging (PET/fMRI) data were collected from 66 patients with TLE and 38 healthy controls (HCs). We compared differences in brain network dynamics between TLE patients and HCs using the multilayer network model constructed from extensive temporal features extracted from fMRI. Postmortem whole brain gene expression data were then utilized to identify genes associated with alterations in TLE connectome dynamics, with subsequent enrichment analysis for functional annotation, cellular, and disease associations. Mediation analysis further explored the interrelations among gene expression, glucose metabolism as measured by PET, and brain network dynamics as measured by fMRI. Compared with HCs, individuals with TLE exhibited increased module variability primarily in the default mode network and reduced module variability in the attention network. These case-control differences were validated through split-half analyses and remained unaffected by medication or lateralization. These aberrant module variability patterns were associated with gene expression profiles predominantly related to inhibitory neurons, postsynaptic cell components, MAPK signaling pathway, and these genes were significantly enriched relative to established epilepsy-related gene sets. Moreover, we observed that the effect of gene expression profile on the alterations in TLE connectome dynamics was significantly mediated by changes in glucose metabolism. These findings highlight that alterations in brain network dynamics in TLE are associated with transcriptomic signatures, and that glucose metabolic changes partially mediate this relationship, furthering insights into the biological basis of the disorder.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106967"},"PeriodicalIF":5.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144120192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term hippocampal low-frequency stimulation alleviates focal seizures, memory deficits and synaptic pathology in epileptic mice","authors":"Piret Kleis ,&nbsp;Enya Paschen ,&nbsp;Andrea Djie-Maletz ,&nbsp;Andreas Vlachos ,&nbsp;Carola A. Haas ,&nbsp;Ute Häussler","doi":"10.1016/j.nbd.2025.106965","DOIUrl":"10.1016/j.nbd.2025.106965","url":null,"abstract":"<div><h3>Background</h3><div>Mesial temporal lobe epilepsy (MTLE) is a prevalent form of focal epilepsy characterized by seizures originating from the hippocampus and adjacent regions. Neurostimulation presents an alternative for surgery-ineligible patients with intractable seizures. However, conventional approaches have limited efficacy and require refinement for better seizure control. While hippocampal low-frequency stimulation (LFS) has shown promising seizure reduction in animal studies and small clinical cohorts, its mechanisms, sex-specific outcomes, and long-term effects remain unknown.</div></div><div><h3>Objectives</h3><div>We aimed to identify the antiepileptic and cognitive outcomes and potential underlying mechanisms of long-term hippocampal LFS in chronically epileptic male and female mice.</div></div><div><h3>Methods</h3><div>We used the intrahippocampal kainate mouse model replicating the features of MTLE: spontaneous seizures, hippocampal sclerosis, and memory deficits. During the chronic phase of epilepsy, we applied 1 Hz electrical LFS in the sclerotic hippocampus 6 h/day, four times/week for 5 weeks and examined its effects on epileptiform activity, spatial memory, and kainate-induced pathological features at cellular and synaptic levels.</div></div><div><h3>Results</h3><div>Long-term hippocampal LFS consistently diminished focal seizures in epileptic male and female mice, with seizure reduction extending beyond the stimulation period. Additionally, long-term LFS relieved spatial memory deficits and reversed pathological modifications at perforant path-dentate granule cell synapses shortly after stimulation. LFS had no significant effect on secondarily generalized seizures, anxiety-like behaviour, neurogenesis, hippocampal sclerosis, or presynaptic vesicles in perforant path fibres.</div></div><div><h3>Conclusion</h3><div>These findings provide clinically relevant insights into the seizure type-specific effects of hippocampal LFS, which, alongside synaptic and behavioural improvements, could contribute to enhanced seizure control and quality of life in MTLE patients.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106965"},"PeriodicalIF":5.1,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144117067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cortical layer-specific abnormalities in auditory responses in a mouse model of Fragile X Syndrome","authors":"Katrina E. Deane ,&nbsp;Devin K. Binder ,&nbsp;Khaleel A. Razak","doi":"10.1016/j.nbd.2025.106963","DOIUrl":"10.1016/j.nbd.2025.106963","url":null,"abstract":"<div><div>Fragile X Syndrome (FXS) is a leading genetic cause of autism spectrum disorders (ASD)- associated behaviors, including sensory processing deficits. Sensory sensitivity and temporal processing deficits in the auditory domain will affect development of language and cognitive functions. The mouse model for FXS, <em>Fmr1</em> KO, has shown remarkably similar auditory processing phenotypes to patients with FXS. In vitro cortical slice recordings show layer-specific differences in <em>Fmr1</em> KO mouse local circuits, but it is unclear how these differences translate to changes in sensory processing. In this study, we used a depth multielectrode to record in vivo spikes and local field potentials across layers of the auditory cortex in <em>Fmr1</em> KO and wildtype mice (WT), converting the latter to current source density (CSD) profiles for improved spatial resolution analysis. We observed reduced CSD sink amplitudes and inter-trial phase coherence, and an increase in trial-to-trial variability for temporally modulated stimuli in the KO mice. Results indicated a differential cortical layer pattern of activity in KO mice, with higher baseline gamma power in superficial and deep layers and higher resting delta and theta power in granular layers. Significantly elevated inter-trial variability was observed for CSD and spikes in KO mice. Auditory steady state responses to clicks or gaps at 40 Hz showed considerable trial-to-trial variability in a layer-specific manner in KO mice. Neural generators in the <em>Fmr1</em> KO mouse auditory cortex failed to detect short gaps in noise, indicating severe temporal processing deficits. Altogether, this study indicates layer-specific cortical mechanisms of sensory hypersensitivity and temporal processing deficits in FXS.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106963"},"PeriodicalIF":5.1,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of melanin and macrophage activation on hearing loss in SLC26A4 deficient mice.","authors":"Natsuki Aoki ,&nbsp;Ayako Maruyama ,&nbsp;Toru Miwa ,&nbsp;Natsuko Kurata ,&nbsp;Keiji Honda ,&nbsp;Yoshiyuki Kawashima ,&nbsp;Takeshi Tsutsumi ,&nbsp;Taku Ito","doi":"10.1016/j.nbd.2025.106962","DOIUrl":"10.1016/j.nbd.2025.106962","url":null,"abstract":"<div><div>Hearing loss associated with <em>SLC26A4</em> mutations exhibits diverse phenotypes, including congenital, acquired, progressive, and fluctuating impairments. This study investigates how pigmentation influences auditory dysfunction and immune responses in the stria vascularis using albino and pigmented <em>Slc26a4</em> knockout (<em>Slc26a4</em>^{<em>Δ/Δ</em>}) mice. We found that albino <em>Slc26a4</em>^{<em>Δ/Δ</em>} mice exhibited significantly less severe hearing loss along with reduced macrophage activation than their pigmented counterpart did. Three-dimensional morphometric analyses revealed that macrophages in pigmented <em>Slc26a4</em>^{<em>Δ/Δ</em>} mice were significantly larger, more rounded, and structurally distinct from those in albino mice, suggesting divergent activation states. PHATE-based trajectory analysis further confirmed that these macrophages follow separate activation pathways influenced by pigmentation. Transcriptomic profiling showed no upregulation of melanogenesis-related genes, implying that melanin accumulation arises from impaired degradation rather than increased synthesis. Functional enrichment analysis highlighted dysregulation in proteolysis and phosphate metabolism, implicating metabolic stress and chronic inflammation in disease progression. Based on these findings, we propose a multi-step pathophysiological cascade in which <em>SLC26A4</em> deficiency leads to metabolic imbalance, pathological melanin accumulation, macrophage activation, and ultimately, progressive hearing loss. This work reveals a context-dependent dual role of melanin and demonstrates how genetic background and pigmentation influence immune responses and cochlear pathology. These insights may inform future strategies for individualized approaches to diagnosis and therapy in <em>SLC26A4</em>-related hearing loss.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106962"},"PeriodicalIF":5.1,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytic AEG-1 drives neuroinflammation and enhances seizure susceptibility","authors":"Yuzhou Chen ,&nbsp;Yunbo Yu ,&nbsp;Jinhao Kou ,&nbsp;Honggang Qi ,&nbsp;Canyu Zhang ,&nbsp;Feiyu Wang ,&nbsp;Lijie Zhou ,&nbsp;Xuemei Liang ,&nbsp;Kang Xu ,&nbsp;Cong Zhang ,&nbsp;Aifeng Zhang ,&nbsp;Xiufang Liu ,&nbsp;Chenchen Zhang ,&nbsp;Guangming Gan ,&nbsp;Jie Sun ,&nbsp;Xinjian Zhu","doi":"10.1016/j.nbd.2025.106957","DOIUrl":"10.1016/j.nbd.2025.106957","url":null,"abstract":"<div><div>Astrocyte-elevated gene-1 (AEG-1), also known as metadherin (MTDH) has emerged as a potent oncogene expressed in cancers. An increasing body of evidence indicates AEG-1 plays a pivotal role in various brain pathophysiological processes. Abnormal expression of AEG-1 in astrocytes has been correlated with inflammatory response, suggesting a possible role of AEG-1 in the pathogenesis of inflammatory encephalopathy. Here, we analyzed single-cell RNA sequencing data to explore the heterogeneity of astrocyte subpopulations in a mouse model induced by lipopolysaccharide (LPS), and investigated the effect of astrocytic AEG-1 on lipopolysaccharide (LPS)-induced inflammatory response and seizure susceptibility in mice, as well as in an <em>in vitro</em> astrocyte culture model. Our single-cell RNA sequencing analysis reveals that AEG-1-expressing astrocyte subpopulation is associated with inflammatory responses. LPS-induced inflammatory response is accompanied by increased AEG-1 expression in astrocytes. Depletion of astrocytic AEG-1, however, suppressed LPS-induced neuroinflammation and high seizure susceptibility both <em>in vivo</em> and <em>in vitro</em>. Furthermore, we find that AEG-1 induces neuroinflammatory cytokine expression and enhances seizure susceptibility, which is dependent on NF-κB signaling pathway. These data identify an important role of astrocytic AEG-1 in LPS-induced neuroinflammation and high seizure susceptibility, demonstrating that AEG-1 mediates downstream neuroinflammatory and epileptic effect <em>via</em> NF-κB signaling pathway.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106957"},"PeriodicalIF":5.1,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144089702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mechanism of disease progression by aging and age-related gut dysbiosis in multiple sclerosis","authors":"Sudhir Kumar Yadav ,&nbsp;Claire Chen ,&nbsp;Suhayl Dhib-Jalbut ,&nbsp;Kouichi Ito","doi":"10.1016/j.nbd.2025.106956","DOIUrl":"10.1016/j.nbd.2025.106956","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is the most common demyelinating disease caused by a multifaceted interplay of genetic predispositions and environmental factors. Most patients initially experience the relapsing-remitting form of the disease (RRMS), which is characterized by episodes of neurological deficits followed by periods of symptom resolution. However, over time, many individuals with RRMS advance to a progressive form of the disease, known as secondary progressive MS (SPMS), marked by a gradual worsening of symptoms without periods of remission. The mechanisms underlying this transition remain largely unclear, and current disease-modifying therapies (DMTs) are partially effective in treating SPMS. Age is widely acknowledged as a risk factor for the transition from RRMS to SPMS. One factor associated with aging that may influence the progression of MS is gut dysbiosis. This review discusses how aging and age-related gut dysbiosis affect the progression of MS.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106956"},"PeriodicalIF":5.1,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternating hemiplegia of childhood associated mutations in Atp1a3 reveal diverse neurological alterations in mice","authors":"Markus Terrey ,&nbsp;Georgii Krivoshein ,&nbsp;Scott I. Adamson ,&nbsp;Elena Arystarkhova ,&nbsp;Laura Anderson ,&nbsp;John Szwec ,&nbsp;Shelby McKee ,&nbsp;Holly Jones ,&nbsp;Sara Perkins ,&nbsp;Vijay Selvam ,&nbsp;Pierre-Alexandre Piec ,&nbsp;Dweet Chhaya ,&nbsp;Ari Dehn ,&nbsp;Aamir Zuberi ,&nbsp;Stephen A. Murray ,&nbsp;Natalia S. Morsci ,&nbsp;Kathleen J. Sweadner ,&nbsp;David A. Knowles ,&nbsp;Else A. Tolner ,&nbsp;Arn M.J.M. van den Maagdenberg ,&nbsp;Cathleen M. Lutz","doi":"10.1016/j.nbd.2025.106954","DOIUrl":"10.1016/j.nbd.2025.106954","url":null,"abstract":"<div><div>Pathogenic variants in the neuronal Na⁺/K⁺ ATPase transmembrane ion transporter (<em>ATP1A3</em>) cause a spectrum of neurological disorders including alternating hemiplegia of childhood (AHC). The most common <em>de novo</em> pathogenic variants in AHC are p.D801N (∼40 % of patients) and p.E815K (∼25 % of patients), which lead to early mortality by spontaneous death in mice. Nevertheless, knowledge of the development of clinically relevant neurological phenotypes without the obstacle of premature death, is critical for the identification of pathophysiological mechanisms and ultimately, for the testing of therapeutic strategies in disease models. Here, we used hybrid vigor attempting to mitigate the fragility of AHC mice and then performed behavioral, electrophysiological, biochemical, and molecular testing to comparatively analyze mice that carry either of the two most common AHC patient observed variants in the <em>Atp1a3</em> gene. Collectively, our data reveal the presence but also the differential impact of the p.D801N and p.E815K variants on disease relevant alterations such as spontaneous and stress-induced paroxysmal episodes, motor function, behavioral and neurophysiological activity, and neuroinflammation. Our alternate AHC mouse models with their phenotypic deficits open novel avenues for the investigation of disease biology and therapeutic testing for ATP1A3 research.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106954"},"PeriodicalIF":5.1,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}