Neurobiology of Disease最新文献

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Functional dynamic network connectivity differentiates biological patterns in the Alzheimer's disease continuum
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-03-11 DOI: 10.1016/j.nbd.2025.106866
Lorenzo Pini , Lorenza Brusini , Alessandra Griffa , Federica Cruciani , Gilles Allali , Giovanni B. Frisoni , Maurizio Corbetta , Gloria Menegaz , Ilaria Boscolo Galazzo , for the Alzheimer's Disease Neuroimaging Initiative
{"title":"Functional dynamic network connectivity differentiates biological patterns in the Alzheimer's disease continuum","authors":"Lorenzo Pini ,&nbsp;Lorenza Brusini ,&nbsp;Alessandra Griffa ,&nbsp;Federica Cruciani ,&nbsp;Gilles Allali ,&nbsp;Giovanni B. Frisoni ,&nbsp;Maurizio Corbetta ,&nbsp;Gloria Menegaz ,&nbsp;Ilaria Boscolo Galazzo ,&nbsp;for the Alzheimer's Disease Neuroimaging Initiative","doi":"10.1016/j.nbd.2025.106866","DOIUrl":"10.1016/j.nbd.2025.106866","url":null,"abstract":"<div><div>Alzheimer's disease (AD) can be conceptualized as a network-based syndrome. Network alterations are linked to the molecular hallmarks of AD, involving amyloid-beta and tau accumulation, and consecutively neurodegeneration. By combining molecular and resting-state functional magnetic resonance imaging, we assessed whether different biological patterns of AD identified through a data-driven approach matched specific abnormalities in brain dynamic connectivity. We identified three main patient clusters. The first group displayed mild pathological alterations. The second cluster exhibited typical behavioral impairment alongside AD pathology. The third cluster demonstrated similar behavioral impairment but with a divergent tau (low) and neurodegeneration (high) profile. Univariate and multivariate analyses revealed two connectivity patterns encompassing the default mode network and the occipito-temporal cortex, linked respectively with typical and atypical patterns. These results support the key association between macro-scale and molecular alterations. Dynamic connectivity markers can assist in identifying patients with AD-like clinical profiles but with different underlying pathologies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106866"},"PeriodicalIF":5.1,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143621465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Microstructural and functional abnormalities of the locus coeruleus in freezing of gait in Parkinson's disease
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-03-09 DOI: 10.1016/j.nbd.2025.106868
Huimin Sun , Caiting Gan , Xingyue Cao , Yongsheng Yuan , Heng Zhang , Chenhui Wan , Jiaxin Shi , Xufeng Wang , Youyong Kong , Tao Feng , Kezhong Zhang
{"title":"Microstructural and functional abnormalities of the locus coeruleus in freezing of gait in Parkinson's disease","authors":"Huimin Sun ,&nbsp;Caiting Gan ,&nbsp;Xingyue Cao ,&nbsp;Yongsheng Yuan ,&nbsp;Heng Zhang ,&nbsp;Chenhui Wan ,&nbsp;Jiaxin Shi ,&nbsp;Xufeng Wang ,&nbsp;Youyong Kong ,&nbsp;Tao Feng ,&nbsp;Kezhong Zhang","doi":"10.1016/j.nbd.2025.106868","DOIUrl":"10.1016/j.nbd.2025.106868","url":null,"abstract":"<div><h3>Objective</h3><div>The loss of locus coeruleus (LC)-norepinephrine system may contribute to freezing of gait (FOG) in Parkinson's disease (PD), but free-water (FW) imaging has not been applied to investigate LC microstructural degeneration in FOG. This study was to investigate the role of the LC-norepinephrine system in FOG pathophysiology using FW imaging and resting-state functional magnetic resonance imaging.</div></div><div><h3>Methods</h3><div>FW metrics of LC were analyzed in 52 healthy controls, 79 PD patients without FOG (Non-FOG), and 110 PD patients with FOG (48 “Off-period” FOG and 62 “Levodopa unresponsive” FOG). Correlation between LC FW metrics and clinical scales were assessed. Functional connectivity analysis with LC as the region of interest was performed across groups during medication withdrawal. Structural and functional differences in LC between FOG subgroups and the effects of dopaminergic medication were also explored.</div></div><div><h3>Results</h3><div>FOG patients had increased FW value, FW-corrected mean diffusivity, axial diffusivity, and radial diffusivity in LC, and decreased FW-corrected fractional anisotropy compared to Non-FOG patients and healthy controls. In FOG patients, FW value and FW-corrected mean axial diffusivity were positively correlated with the new FOG questionnaire scores. LC functional connectivity with occipital regions was reduced in FOG patients. No significant differences in LC microstructure or functional connectivity were observed between FOG subgroups during their “OFF” state. In contrast to “Levodopa-unresponsive” FOG patients, oral medication significantly improved LC functional connectivity with occipital regions in “Off-period” FOG patients.</div></div><div><h3>Conclusions</h3><div>LC degeneration may disrupt motor and compensatory network integration, especially in visual-motor pathways, contributing to FOG.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106868"},"PeriodicalIF":5.1,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dual action of sphingosine 1-phosphate pathway in in vitro models of global cerebral ischemia
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-03-09 DOI: 10.1016/j.nbd.2025.106865
Costanza Mazzantini , Martina Venturini , Daniele Lana , Gloria Mulas , Clara Santalmasi , Giada Magni , Paola Bruni , Anna Maria Pugliese , Francesca Cencetti , Domenico E. Pellegrini-Giampietro , Elisa Landucci
{"title":"Dual action of sphingosine 1-phosphate pathway in in vitro models of global cerebral ischemia","authors":"Costanza Mazzantini ,&nbsp;Martina Venturini ,&nbsp;Daniele Lana ,&nbsp;Gloria Mulas ,&nbsp;Clara Santalmasi ,&nbsp;Giada Magni ,&nbsp;Paola Bruni ,&nbsp;Anna Maria Pugliese ,&nbsp;Francesca Cencetti ,&nbsp;Domenico E. Pellegrini-Giampietro ,&nbsp;Elisa Landucci","doi":"10.1016/j.nbd.2025.106865","DOIUrl":"10.1016/j.nbd.2025.106865","url":null,"abstract":"<div><div>It is well accepted that sphingolipids play an important role in the pathological process of cerebral ischemia. In the present study we have investigated the involvement of sphingosine 1-phosphate (S1P) pathway in two different in vitro models of global ischemia.</div><div>In organotypic hippocampal slices exposed to oxygen and glucose deprivation (OGD) we evaluated the mRNA expression of S1P metabolic enzymes and receptors (S1P<sub>1–5</sub>) by Real Time-PCR. In the same model we investigated the effect of the inhibitor of S1P lyase (SPL), LX2931, the selective antagonists of S1P<sub>2</sub>, JTE-013, and S1P<sub>3</sub>, CAY10444, quantifying the cell death in the CA1 region by propidium iodide fluorescence, and morphological and tissue organization alterations by immunohistochemistry and confocal microscopy. Moreover, we performed extracellular recordings of field excitatory postsynaptic potentials in acute slices exposed to OGD.</div><div>In organotypic slices OGD induced a significant increase of SPL at mRNA level and of S1P<sub>2</sub> and S1P<sub>3</sub> at both mRNA and protein level. The incubation with LX2931, JTE-013 or CAY10444 was able to reduce CA1 damage induced by OGD in organotypic slices and provoked a significant delay of the onset of anoxic depolarization on acute slices. Moreover, S1P<sub>2</sub> and S1P<sub>3</sub> antagonists prevented the increase of TREM2 induced by OGD.</div><div>Our results reveal a dual role of S1P pathway in brain ischemia: intracellular S1P, degraded via SPL, appears to be beneficial whereas signaling via S1P<sub>2</sub> and S1P<sub>3</sub> is detrimental to the disease. These findings support the notion that SPL, S1P<sub>2</sub> and S1P<sub>3</sub> are promising therapeutic targets in brain ischemia.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106865"},"PeriodicalIF":5.1,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Differential miRNA expression in neural-enriched extracellular vesicles as potential biomarker for frontotemporal dementia and bipolar disorder
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-03-09 DOI: 10.1016/j.nbd.2025.106867
Maria Serpente , Giuseppe Delvecchio , Chiara Fenoglio , Lorena Di Consoli , Giulia Giudici , Vittoria Borracci , Emanuela Rotondo , Marina Arcaro , Luca Sacchi , Manuela Pintus , Laura Ghezzi , Adele Ferro , Cecilia Prunas , Antonio Callari , Elisa Scola , Fabio M. Triulzi , Andrea Arighi , Paolo Brambilla , Daniela Galimberti
{"title":"Differential miRNA expression in neural-enriched extracellular vesicles as potential biomarker for frontotemporal dementia and bipolar disorder","authors":"Maria Serpente ,&nbsp;Giuseppe Delvecchio ,&nbsp;Chiara Fenoglio ,&nbsp;Lorena Di Consoli ,&nbsp;Giulia Giudici ,&nbsp;Vittoria Borracci ,&nbsp;Emanuela Rotondo ,&nbsp;Marina Arcaro ,&nbsp;Luca Sacchi ,&nbsp;Manuela Pintus ,&nbsp;Laura Ghezzi ,&nbsp;Adele Ferro ,&nbsp;Cecilia Prunas ,&nbsp;Antonio Callari ,&nbsp;Elisa Scola ,&nbsp;Fabio M. Triulzi ,&nbsp;Andrea Arighi ,&nbsp;Paolo Brambilla ,&nbsp;Daniela Galimberti","doi":"10.1016/j.nbd.2025.106867","DOIUrl":"10.1016/j.nbd.2025.106867","url":null,"abstract":"<div><div>Behavioral variant of Frontotemporal Dementia (bvFTD) and Bipolar Disorder (BD) share overlapping symptoms, complicating diagnosis. BvFTD, especially linked to C9orf72 expansions, often mimics BD, highlighting the need for reliable biomarkers. This study aimed to differentiate bvFTD from BD using miRNA profiles in neural-enriched extracellular vesicles (NEVs). A cohort of 100 subjects was analyzed: 40 bvFTD (20 sporadic, 20 C9orf72 carriers), 40 BD, and 20 healthy controls. NEVs were isolated from plasma and profiled using real-time PCR. Among 754 miRNAs, 11 were significantly deregulated in bvFTD and BD. MiR-152-5p was downregulated in sporadic bvFTD, while let-7b, let-7e, miR-18b, and miR-142-5p were altered in C9orf72 carriers. BD patients showed distinct patterns in miR-331-5p, miR-335, and miR-345 compared to bvFTD. Bioinformatics analyses revealed that let-7e, let-7b, miR-18b, and miR-142-5p share common long non-coding RNA (lncRNA) targets, including XIST, NEAT1, and OIP5-AS1, suggesting their involvement in molecular networks relevant to C9orf72-related bvFTD. These miRNA signatures can differentiate bvFTD from BD, especially in C9orf72-related cases, and offer insights into disease pathways. Further research is needed to validate these findings and explore their clinical application.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106867"},"PeriodicalIF":5.1,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Impaired folate metabolism reshapes auditory response profiles and impairs loudness perception in MTHFR-deficient mice
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-03-07 DOI: 10.1016/j.nbd.2025.106863
Hila Sapir , Ghattas Bisharat , Hava Golan , Jennifer Resnik
{"title":"Impaired folate metabolism reshapes auditory response profiles and impairs loudness perception in MTHFR-deficient mice","authors":"Hila Sapir ,&nbsp;Ghattas Bisharat ,&nbsp;Hava Golan ,&nbsp;Jennifer Resnik","doi":"10.1016/j.nbd.2025.106863","DOIUrl":"10.1016/j.nbd.2025.106863","url":null,"abstract":"<div><div>Folate metabolism, regulated by methylenetetrahydrofolate reductase (MTHFR), is crucial for proper neurodevelopment, and disruptions—whether due to genetic polymorphisms or maternal nutritional deficits—have been linked to cognitive and behavioral impairments. Notably, MTHFR-deficient mouse models display altered social interaction and auditory communication, hinting at disruptions in auditory-related circuits and prompting the question of whether impaired folate metabolism might also affect sound processing and perception. Here, using two-photon calcium imaging, we show that MTHFR deficiency increases both spontaneous and sound-evoked activity in the auditory cortex and significantly shifts neuronal response profiles, which in turn elevates perceived loudness while reducing sound-level discrimination. These findings underscore the potential role of compromised folate metabolism in driving the atypical auditory responses and may have broader relevance for understanding sensory dysfunction in various neurodevelopmental conditions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106863"},"PeriodicalIF":5.1,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-03-04 DOI: 10.1016/j.nbd.2025.106862
Yifei Zheng , Jiahui Yang , Xuanyao Li , Linjie Qi , Zhuo Zheng , Jiming Kong , Guohui Zhang , Ying Guo
{"title":"Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration","authors":"Yifei Zheng ,&nbsp;Jiahui Yang ,&nbsp;Xuanyao Li ,&nbsp;Linjie Qi ,&nbsp;Zhuo Zheng ,&nbsp;Jiming Kong ,&nbsp;Guohui Zhang ,&nbsp;Ying Guo","doi":"10.1016/j.nbd.2025.106862","DOIUrl":"10.1016/j.nbd.2025.106862","url":null,"abstract":"<div><div>Mitochondria play a central role in essential cellular processes, including energy metabolism, biosynthesis of metabolic substances, calcium ion storage, and regulation of cell death. Maintaining mitochondrial quality control is critical for preserving mitochondrial health and ensuring cellular function. Given their high energy demands, neurons depend on effective mitochondrial quality control to sustain their health and functionality. Neuronal senescence, characterized by a progressive decline in structural integrity and function, is a hallmark of neurodegenerative diseases. In senescent neurons, abnormal mitochondrial morphology, functional impairments, increased reactive oxygen species production and disrupted quality control mechanisms are frequently observed. Understanding the pathological changes in neuronal structure, exploring the intricate relationship between mitochondrial quality control and neuronal health, and leveraging mitochondrial quality control interventions provide a promising foundation for addressing age-related neurodegenerative diseases. This review highlights key mitochondrial quality control, including biogenesis, dynamics, the ubiquitin-proteasome system, autophagy pathways, mitochondria-derived vesicles, and inter-organelle communication, while discussing their roles in neuronal senescence and potential therapeutic strategies. These insights may pave the way for innovative treatments to mitigate neurodegenerative disorders.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106862"},"PeriodicalIF":5.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-03-02 DOI: 10.1016/j.nbd.2025.106861
A. Peck , A. Dadi , Z. Yavarow , L.N. Alfano , D. Anderson , M.R. Arkin , T.F. Chou , E.S. D'Ambrosio , J. Diaz-Manera , J.P. Dudley , A.G. Elder , N. Ghoshal , C.E. Hart , M.M. Hart , D.M. Huryn , A.E. Johnson , K.B. Jones , V. Kimonis , E. Kiskinis , E.B. Lee , N. Peck
{"title":"2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy","authors":"A. Peck ,&nbsp;A. Dadi ,&nbsp;Z. Yavarow ,&nbsp;L.N. Alfano ,&nbsp;D. Anderson ,&nbsp;M.R. Arkin ,&nbsp;T.F. Chou ,&nbsp;E.S. D'Ambrosio ,&nbsp;J. Diaz-Manera ,&nbsp;J.P. Dudley ,&nbsp;A.G. Elder ,&nbsp;N. Ghoshal ,&nbsp;C.E. Hart ,&nbsp;M.M. Hart ,&nbsp;D.M. Huryn ,&nbsp;A.E. Johnson ,&nbsp;K.B. Jones ,&nbsp;V. Kimonis ,&nbsp;E. Kiskinis ,&nbsp;E.B. Lee ,&nbsp;N. Peck","doi":"10.1016/j.nbd.2025.106861","DOIUrl":"10.1016/j.nbd.2025.106861","url":null,"abstract":"<div><div>Valosin-containing protein (VCP/p97) is a ubiquitously expressed AAA+ ATPase associated with numerous protein-protein interactions and critical cellular functions including protein degradation and clearance, mitochondrial homeostasis, DNA repair and replication, cell cycle regulation, endoplasmic reticulum-associated degradation, and lysosomal functions including autophagy and apoptosis. Autosomal-dominant missense mutations in the <em>VCP</em> gene may result in VCP-associated multisystem proteinopathy (VCP-MSP), a rare degenerative disorder linked to heterogeneous phenotypes including inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and frontotemporal dementia (FTD) or IBMPFD, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), parkinsonism, Charcot-Marie Tooth disease (CMT), and spastic paraplegia. The complexity of VCP-MSP makes collaboration among stakeholders essential and necessitates a multi-disciplinary approach.</div><div>The 2024 VCP International Conference was hosted at Caltech between February 22 and 25. Co-organized by Cure VCP Disease and Dr. Tsui-Fen Chou, the meeting aimed to center the patient as a research partner, harmonize diverse stakeholder engagement, and bridge the gap between basic and clinical neuroscience as it relates to VCP-MSP. Over 100 multi-disciplinary experts attended, ranging from basic scientists to clinicians to patient advocates. Attendees discussed genetics and clinical presentation, cellular and molecular mechanisms underlying disease, therapeutic approaches, and strategies for future VCP research. The conference included three roundtable discussions, 29 scientific presentations, 32 scientific posters, nine patient and caregiver posters, and a closing discussion forum. The following conference proceedings summarize these sessions, highlighting both the identified gaps in knowledge and the significant strides made towards understanding and treating VCP diseases.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106861"},"PeriodicalIF":5.1,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Leveraging animal models to understand non-motor symptoms of Parkinson's disease
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-02-27 DOI: 10.1016/j.nbd.2025.106848
Thomas Wichmann , Alexandra Nelson , Eileen Ruth S. Torres , Per Svenningsson , Roberta Marongiu
{"title":"Leveraging animal models to understand non-motor symptoms of Parkinson's disease","authors":"Thomas Wichmann ,&nbsp;Alexandra Nelson ,&nbsp;Eileen Ruth S. Torres ,&nbsp;Per Svenningsson ,&nbsp;Roberta Marongiu","doi":"10.1016/j.nbd.2025.106848","DOIUrl":"10.1016/j.nbd.2025.106848","url":null,"abstract":"<div><div>Parkinson's disease is diagnosed based on motor symptoms, but non-motor symptoms of the disease, such as cognitive impairment, autonomic dysfunction, hyposmia, sleep disorders, and psychiatric disorders heavily impact patient and caregiver quality of life. It has proven challenging to faithfully reproduce and quantify these non-motor phenotypes. Indeed, many non-motor signs in animals that may phenotypically resemble features in patients may be caused by different mechanisms or may not be consistent within the same or similar models. In this review, we survey the existing literature on the assessment of non-motor signs in parkinsonian rodents and non-human primates. We highlight the gaps in our understanding and suggest how researchers might improve experimental designs to produce more meaningful results with the hope of better understanding the disease and developing better therapies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"208 ","pages":"Article 106848"},"PeriodicalIF":5.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-02-26 DOI: 10.1016/j.nbd.2025.106853
Lara Pizzamiglio , Fabrizio Capitano , Evgeniia Rusina , Giuliana Fossati , Elisabetta Menna , Isabelle Léna , Flavia Antonucci , Massimo Mantegazza
{"title":"Neurodevelopmental defects in Dravet syndrome Scn1a+/− mice: Targeting GABA-switch rescues behavioral dysfunctions but not seizures and mortality","authors":"Lara Pizzamiglio ,&nbsp;Fabrizio Capitano ,&nbsp;Evgeniia Rusina ,&nbsp;Giuliana Fossati ,&nbsp;Elisabetta Menna ,&nbsp;Isabelle Léna ,&nbsp;Flavia Antonucci ,&nbsp;Massimo Mantegazza","doi":"10.1016/j.nbd.2025.106853","DOIUrl":"10.1016/j.nbd.2025.106853","url":null,"abstract":"<div><div>Dravet syndrome (DS) is a developmental and epileptic encephalopathy (DEE) caused by mutations of the <em>SCN1A</em> gene (Na<sub>V</sub>1.1 sodium channel) and characterized by seizures, motor disabilities and cognitive/behavioral deficits, including autistic traits. The relative role of seizures and neurodevelopmental defects in disease progression, as well as the role of the mutation in inducing early neurodevelopmental defects before symptoms' onset, are not clear yet. A delayed switch of GABAergic transmission from excitatory to inhibitory (GABA-switch) was reported in models of DS, but its effects on the phenotype have not been investigated.</div><div>Using a multi-scale approach, here we show that targeting GABA-switch with the drugs KU55933 (KU) or bumetanide (which upregulate KCC2 or inhibits NKCC1 chloride transporters, respectively) rescues social interaction deficits and reduces hyperactivity observed in P21 <em>Scn1a</em><sup><em>+/−</em></sup> DS mouse model. Bumetanide also improves spatial working memory defects. Importantly, neither KU nor bumetanide have effect on seizures or mortality rate. Also, we disclose early behavioral defects and delayed neurodevelopmental milestones well before seizure onset, at the beginning of Na<sub>V</sub>1.1 expression.</div><div>We thus reveal that neurodevelopmental components in DS, in particular GABA switch, underlie some cognitive/behavioral defects, but not seizures. Our work provides further evidence that seizures and neuropsychiatric dysfunctions in DEEs can be uncoupled and can have differential pathological mechanisms. They could be treated separately with targeted pharmacological strategies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106853"},"PeriodicalIF":5.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Potentiation of the M1 muscarinic acetylcholine receptor normalizes neuronal activation patterns and improves apnea severity in Mecp2+/− mice
IF 5.1 2区 医学
Neurobiology of Disease Pub Date : 2025-02-26 DOI: 10.1016/j.nbd.2025.106859
Mackenzie Smith , Grace E. Dodis , Amanda M. Vanderplow , Sonia Gonzalez , Yewon Rhee , Karie Scrogin , Rocco G. Gogliotti
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