Neurobiology of Disease最新文献

{"title":"Global Grin2a loss causes divergent impairments to PV+ and SST+ interneurons and alters gamma oscillations in prefrontal cortex","authors":"Hassan Hosseini ,&nbsp;Sky Evans-Martin ,&nbsp;Kevin S. Jones","doi":"10.1016/j.nbd.2025.106977","DOIUrl":"10.1016/j.nbd.2025.106977","url":null,"abstract":"<div><h3>Background</h3><div>Loss-of-function mutations in the <em>Grin2a</em> gene, encoding the GluN2A subunit of NMDA receptors, confer elevated schizophrenia (SCZ) risk. Although GluN2A is expressed in multiple interneuron subtypes, its role in inhibitory circuit function remains incompletely understood. Recent genetic and transcriptomic studies implicate somatostatin-positive (SST⁺) interneurons in SCZ pathophysiology, raising the question of whether <em>Grin2a</em> deletion differentially affects SST⁺ and parvalbumin-positive (PV⁺) cells.</div></div><div><h3>Methods</h3><div>We utilized global <em>Grin2a</em> knockout (KO) and heterozygous (HET) mice to investigate how GluN2A deficiency affects inhibitory dynamics in the prelimbic (PrL) medial prefrontal cortex (mPFC). Immunohistochemistry quantified interneuron density, while slice electrophysiology and optogenetics assessed inhibitory postsynaptic current (IPSC) amplitude and kinetics, quantal GABA release, and PV⁺- and SST-driven gamma-band oscillations (GBOs).</div></div><div><h3>Results</h3><div><em>Grin2a</em> KO and HET mice exhibited increased PV⁺ and SST⁺ interneuron density and a shift in excitatory–inhibitory (E/I) balance favoring inhibition. PV⁺ interneurons displayed functional impairments characterized by prolonged IPSC decay, elevated asynchronous GABA release, and enhanced PV-driven gamma-band oscillations (GBOs), consistent with impaired presynaptic calcium handling. In contrast, SST⁺ interneurons exhibited increased IPSC amplitudes without alterations in short-term plasticity or oscillatory drive, suggesting modulation of inhibitory tone without affecting network synchrony.</div></div><div><h3>Conclusion</h3><div>GluN2A loss appears to disrupt inhibitory networks through distinct cell-type-specific mechanisms—presynaptic dysfunction in PV⁺ cells and postsynaptic enhancement from SST⁺ cells. PV⁺ dysfunction aligns with gamma synchrony impairments linked to SCZ cognitive flexibility, while SST⁺ alterations may contribute to impaired feedback inhibition and sensory deficits. These findings clarify GluN2A's role in interneuron subtype function and network stability in SCZ.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106977"},"PeriodicalIF":5.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174083","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 chaperones HSP90AA1, HSP90AB1 and BAG3 are specifically distributed among human hippocampal subfields during different Alzheimer's disease stages","authors":"Carmen Soriano-Herrador ,&nbsp;Isabel Ubeda-Banon ,&nbsp;Patricia Villanueva-Anguita ,&nbsp;Daniel Saiz-Sanchez ,&nbsp;Veronica Astillero-Lopez ,&nbsp;Alino Martinez-Marcos ,&nbsp;Alicia Flores-Cuadrado","doi":"10.1016/j.nbd.2025.106971","DOIUrl":"10.1016/j.nbd.2025.106971","url":null,"abstract":"<div><div>Alzheimer's disease (AD) includes amyloid-β plaques and tau tangles as associated proteinopathies. Tau aggregates appear in a sequential and predictable manner, defined by six stages (Braak stages I–VI) of neuropathological diagnosis, with the hippocampus, particularly the CA1 subfield, being involved in the early stages. Chaperones play a key role in amyloid-β and tau misfolding. Chaperones constitute a vast family of proteins, but proteomic assays have indicated that HSP90AA1, HSP90AB1 and BAG3 are differentially expressed in the hippocampus of human AD patients. However, it is unknown whether the distribution of these proteins changes across different hippocampal subfields and/or in different neuropathological stages. Therefore, the distributions of the HSP90AA1, HSP90AB1 and BAG3 chaperones across hippocampal subfields (CA1, CA2, CA3 and DG) and across neuropathological stages (non-AD, 0; initial-AD, I-I; intermediate-AD, III–IV; and advanced-AD, V–VI) were stereologically quantified using the Area Fraction Fractionator probe. The area fraction of HSP90AA1 was lower in CA1 in advanced stages, whereas that of HSP90AB1 was greater in CA2 in advanced stages. In contrast, the area fraction of BAG3 was greater in CA1, CA3 and the DG between the non-AD and initial-AD stages but was lower in the DG in the intermediate-AD stage. This finding suggests that chaperone dysregulation could be responsible for the altered clearance and increased pathological misfolding that is observed in AD, leading to differential subfield vulnerability. Indeed, these chaperones could be useful as predictive biomarkers or therapeutic targets for AD because of their differential distribution across subfields and stages, which may increase the sensitivity and specificity of these proteins for use in these ways.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106971"},"PeriodicalIF":5.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144154913","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":"Imbalanced mitochondrial dynamics in human PD and α-synuclein mouse brains","authors":"Harry J. Brown ,&nbsp;Rebecca Z. Fan ,&nbsp;Riley Bell ,&nbsp;Said S. Salehe ,&nbsp;Carlos Martínez Martínez ,&nbsp;Yanhao Lai ,&nbsp;Kim Tieu","doi":"10.1016/j.nbd.2025.106976","DOIUrl":"10.1016/j.nbd.2025.106976","url":null,"abstract":"<div><div>Emerging studies have shown that dysregulation in mitochondrial dynamics has a major negative impact on mitochondria. Partial genetic and pharmacological inhibition of the mitochondrial fission dynamin-related protein 1 (DRP1) has been demonstrated to be beneficial in models of neurodegenerative disorders, including Parkinson's disease (PD). However, the expression of DRP1 and other mitochondrial fission/fusion mediators have not been investigated in the brains of Parkinson's patients. This information is critical to strengthening mitochondrial dynamics as a potential therapeutic target for PD. We report in this study that significant increases in the levels of both <em>DNM1L,</em> which encodes DRP1, as well as the DRP1 protein were detected in Parkinson's patients. Immunostaining revealed increased DRP1 expression in dopamine (DA) neurons, astrocytes, and microglia. In addition to DRP1, the levels of other fission and fusion genes/proteins were also altered. To complement these human studies and given the significant role of α-synuclein in PD pathogenesis, we performed time-course studies using transgenic mice overexpressing human wild-type <em>SNCA</em>. As early as six months old, we detected an upregulation of DRP1 in the nigral DA neurons of the <em>SNCA</em> mice as compared to their wild-type littermates. Furthermore, these mutant animals exhibited more DRP1 phosphorylation at serine 616, which promotes its translocation to mitochondria to induce fragmentation. Together, this study shows an upregulation of DRP1 and alterations in other fission/fusion proteins in both human and mouse PD brains, leading to a pro-fission phenotype, providing additional evidence that blocking mitochondrial fission or promoting fusion is a potential therapeutic strategy for PD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106976"},"PeriodicalIF":5.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144168260","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":"Exploring the impact of SerpinA3n deficiency on prion strains propagation","authors":"Fabio Moda ,&nbsp;Chiara Ferracin ,&nbsp;Ilaria Linda Dellarole ,&nbsp;Edoardo Bistaffa ,&nbsp;Chiara Maria Giulia De Luca ,&nbsp;Marco Zattoni ,&nbsp;Diletta Giovanna Legari ,&nbsp;Lea Nikolic ,&nbsp;Anna Burato ,&nbsp;Martina Brce ,&nbsp;Giuseppe Bufano ,&nbsp;Merve Begüm Bacınoğlu ,&nbsp;Federico Angelo Cazzaniga ,&nbsp;Tihana Lenac Rovis ,&nbsp;Giuseppe Legname","doi":"10.1016/j.nbd.2025.106973","DOIUrl":"10.1016/j.nbd.2025.106973","url":null,"abstract":"<div><div>Transmissible spongiform encephalopathies (TSEs) are a group of devastating neurodegenerative diseases characterized by the conversion of the normal cellular prion protein (PrP^C) into its misfolded, pathogenic form, PrP^Sc. Despite significant research, the exact molecular mechanisms driving PrP^C to PrP^Sc conversion remain elusive and are thought to involve multiple molecules or cofactors. One protein of interest, SERPINA3 (murine SerpinA3n), is an acute-phase protein, a member of the serine protease inhibitor family. Intriguingly, SERPINA3 expression is notably upregulated in the brains of patients with Creutzfeldt-Jakob disease and in mice experimentally infected with prions, suggesting a potential role in prion disease pathology. In this study, we deepened the role of SerpinA3n in prion conversion and propagation by utilizing SerpinA3n-deficient (SerpinA3n^−/−) mice intracerebrally injected with the RML, 139A, or ME7 prion strains. Our results showed that the specific absence of SerpinA3n did not significantly affect prion propagation, as evidenced by the lack of notable changes in clinical and neuropathological assessments. Compensatory mechanisms involving other serpins or molecules may mitigate the effects of the specific absence of SerpinA3n, thereby maintaining efficient prion propagation.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106973"},"PeriodicalIF":5.1,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160640","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":"Data-driven, cross-sectional image-based subtyping and staging of brain volumetric changes in Parkinson's disease","authors":"Gilsoon Park ,&nbsp;Jongmok Ha ,&nbsp;Jun Seok Lee ,&nbsp;Jong Hyeon Ahn ,&nbsp;Jin Whan Cho ,&nbsp;Sang Won Seo ,&nbsp;Jinyoung Youn ,&nbsp;Hosung Kim","doi":"10.1016/j.nbd.2025.106970","DOIUrl":"10.1016/j.nbd.2025.106970","url":null,"abstract":"<div><h3>Background</h3><div>Several subtyping methods have been proposed to characterize Parkinson's disease (PD) progression, yet the trajectory of subcortical and cortical neurodegeneration and its clinical implications remain unclear.</div></div><div><h3>Objectives</h3><div>We aimed to conduct a strictly image-based, data-driven classification of PD progression through Subtype and Stage Inference (SuStaIn) algorithm.</div></div><div><h3>Methods</h3><div>Brain volumetric data from 565 patients with PD and 150 propensity-matched healthy controls were analyzed. 16 regions of interest, including 9 cortical and 7 deep grey matter structures, were segmented from T1-weighted magnetic resonance images. Clinical data, including REM sleep behavior disorder (RBD), levodopa equivalent daily dose (LEDD), and motor complications were collected. SuStaIn was trained and tested using a 10-folds cross-validation and identified two distinct PD progression subtypes, which were compared for differences in clinical and radiological characteristics.</div></div><div><h3>Results</h3><div>We found two distinct neurodegenerative trajectories: deep grey matter (DG)-first and cortex (CO)-first. The CO-first subtype had a higher prevalence of RBD (<em>p</em> = 0.009) and levodopa-induced dyskinesia (<em>p</em> = 0.024) than the DG-first subtype. Disease progression was faster in the CO-first subtype (0.203 year/stage, LEDD increase 59.3 mg/year), than in the DG-first subtype (0.081 year/stage, LEDD increase 45.1 mg/year, respectively). Regardless of the subtypes, the sensorimotor and auditory cortices were the earliest affected cortical regions, while the amygdala was the first affected subcortically. A subset of participants (<em>n</em> = 186) showed no significant atrophy progression.</div></div><div><h3>Conclusions</h3><div>Our findings support the existence of two distinct subtypes of PD progression based on neuroimaging data. Longitudinal studies are warranted to track their evolution.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106970"},"PeriodicalIF":5.1,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151367","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":"A primer on copper biology in the brain","authors":"Alicia R. Lane ,&nbsp;Blaine R. Roberts ,&nbsp;Christoph J. Fahrni ,&nbsp;Victor Faundez","doi":"10.1016/j.nbd.2025.106974","DOIUrl":"10.1016/j.nbd.2025.106974","url":null,"abstract":"<div><div>This primer aims to expose scientists who study the brain to the field of copper biology. We briefly discuss key copper homeostasis mechanisms and proteins and place these functions in the context of the brain and neurodevelopment. A small number of key copper genes are explored as representative examples of the importance of this metal to the brain. We show that these genes are expressed throughout the brain and their defects are linked to a diverse array of neurological phenotypes, which we discuss further in the context of several neurological and neurodegenerative diseases associated with dysregulation of copper. This review aims to expose interested scientists to the fundamental roles for copper in the brain, the primary proteins responsible for maintaining copper homeostasis in the brain, and the classic neurological diseases associated with this metal.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106974"},"PeriodicalIF":5.1,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143243","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":"Activation of PDE2A moderates pathologically high cAMP/PKA responses to dopamine in dyskinetic mice","authors":"Ségolène Bompierre ,&nbsp;Cédric Yapo ,&nbsp;Régis Blaise ,&nbsp;Pierre Vincent ,&nbsp;Liliana R.V. Castro","doi":"10.1016/j.nbd.2025.106968","DOIUrl":"10.1016/j.nbd.2025.106968","url":null,"abstract":"<div><div>Dopamine depletion in Parkinson's disease (PD) leads to severe motor and cognitive disturbances. While L-DOPA replacement therapy efficiently alleviates the motor symptoms, it leads to long-term complications, notably dyskinesia. These deregulations are closely associated with an exacerbated cAMP/PKA signaling and alterations in striatal plasticity. In this study we used genetically encoded biosensors to monitor cAMP and PKA signals in the 6-OHDA mouse model of Parkinson's disease. In these mice cAMP levels and PKA signaling were markedly up-regulated. We observed that stimulation of the cGMP signaling by a NO donor, DEANO, efficiently down-regulated the amplitude of these hypersensitive responses and this regulatory effect was mediated by PDE2A. Indeed, the stimulation of PDE2A by cGMP was found to efficiently reduce the excessive cAMP/PKA signaling triggered by D₁ receptor stimulation, and this, despite unaltered PDE2A expression. These findings strongly suggest that boosting PDE2A activity in the striatum would be of therapeutic value to moderate the excessive cAMP/PKA responses and mitigate the long-term changes in striatal neurons associated with the adverse effects of L-DOPA treatment.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106968"},"PeriodicalIF":5.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143245","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":"Muscle theta activity in the pathophysiology of cervical dystonia","authors":"Giorgio Leodori ,&nbsp;Giulia Ruocco ,&nbsp;Nicoletta Manzo ,&nbsp;Danny Spampinato ,&nbsp;Gina Ferrazzano ,&nbsp;Francesco Marchet ,&nbsp;Daniele Belvisi ,&nbsp;Jürgen Konczak ,&nbsp;Giovanni Fabbrini ,&nbsp;Alfredo Berardelli ,&nbsp;Antonella Conte","doi":"10.1016/j.nbd.2025.106969","DOIUrl":"10.1016/j.nbd.2025.106969","url":null,"abstract":"<div><h3>Background</h3><div>Increased theta-band intermuscular coherence (IMC) between neck muscles has been reported as pathophysiological features of cervical dystonia (CD).</div></div><div><h3>Objectives</h3><div>investigate whether increased theta power and IMC are specific to the affected muscles, cortically driven, and actively contribute to dystonic contractions by examining the effect of sensory trick (ST) and analyzing correlations with clinical severity.</div></div><div><h3>Methods</h3><div>29 patients with torticollis (13 with effective ST) and 14 healthy subjects (HS) participated. We recorded EMG from bilateral sternocleidomastoid (SCM) and biceps (BIC) muscles and EEG over sensorimotor cortex. Theta power, IMC, and corticomuscular coherence (CMC) were analyzed across baseline and touch conditions and correlated with Torticollis Severity Scale (TSS) scores. Granger causality was used to assess the directionality of coherence.</div></div><div><h3>Results</h3><div>patients exhibited increased theta power in SCMs but not in biceps muscles. Theta IMC was significantly higher only between bilateral SCMs in CD compared to HS. We found no group differences in theta CMC, with Granger causality indicating predominant theta connectivity from muscle to cortex. The ST was associated with increased theta IMC between SCMs, while patients without ST showed a significant reduction in IMC. SCM theta power and IMC were both inversely correlated with TSS.</div></div><div><h3>Conclusions</h3><div>increased theta power and IMC in SCMs are specific to CD and likely reflect a subcortical drive rather than a cortical influence. Our results challenge prior suggestions of a pathogenic role for muscle theta synchronization in CD and suggest a possible compensatory role in balancing head position.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106969"},"PeriodicalIF":5.1,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144132145","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":"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}