Neurobiology of Disease最新文献

{"title":"Tri-modal assessment reveals early visual pathway degeneration in patients with MSA-C","authors":"Chunrong Wang ,&nbsp;Feiyan Deng ,&nbsp;Zhao Chen ,&nbsp;Daji Chen ,&nbsp;Linlin Wan ,&nbsp;Zhe Long ,&nbsp;Riwei Ouyang ,&nbsp;Qi Wu ,&nbsp;Qin Long ,&nbsp;Jiawei He ,&nbsp;Mengyuan Dong ,&nbsp;Linliu Peng ,&nbsp;Huirong Peng ,&nbsp;Yuting Shi ,&nbsp;Xuan Hou ,&nbsp;Lang He ,&nbsp;Rong Qiu ,&nbsp;Beisha Tang ,&nbsp;Hong Jiang","doi":"10.1016/j.nbd.2025.107243","DOIUrl":"10.1016/j.nbd.2025.107243","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Post-mortem evidence suggests neurodegeneration in the visual pathway in multiple system atrophy-cerebellar type (MSA-C), yet robust <em>in vivo</em> evidence remains scarce. This study aimed to characterize these visual pathway changes in MSA-C patients by integrating optical coherence tomography (OCT), visual evoked potential (VEP), and magnetic resonance imaging (MRI).</div></div><div><h3>Methods</h3><div>This cross-sectional study prospectively recruited 156 participants, including 53 healthy controls and 103 early-stage MSA-C patients (mean disease duration: approx. 2 years). All participants underwent retinal layer evaluation using OCT. A randomly selected subset of 34 MSA-C patients and 19 controls also received VEP and MRI to assess visual pathway structure and function comprehensively.</div></div><div><h3>Results</h3><div>OCT analysis revealed significant parafoveal thinning within the 3-mm inner ring in MSA-C patients, predominantly affecting the ganglion cell layer (GCL) (<em>P</em> &lt; 0.001) and inner plexiform layer (IPL) (<em>P</em> &lt; 0.001). VEP recordings demonstrated significantly prolonged P100 latency (<em>P</em> &lt; 0.001). MRI confirmed reduced cerebellar volume (<em>P</em> &lt; 0.001). DTI detected microstructural degeneration in the cerebellum and visual pathways, with increased mean and axial diffusivity in optic tracts and radiation. Notably, retinal thinning correlated significantly with longer P100 latency (GCL: <em>r</em> = 0.49, <em>P</em> = 0.003; IPL: <em>r</em> = 0.41, <em>P</em> = 0.015) and cerebellar atrophy (GCL: <em>r</em> = 0.53, <em>P</em> = 0.001; IPL: r = 0.49, <em>P</em> = 0.003), indicating integrated visual pathway degeneration.</div></div><div><h3>Conclusions</h3><div>This large-scale multimodal study provides robust <em>in vivo</em> evidence that MSA-C involves early retinal neurodegeneration, functional conduction delay, and central white matter degeneration. The convergence of OCT, VEP, and DTI parameters suggests bidirectional retinocortical degeneration. Our findings support the potential of these parameters for early detection and highlight the visual pathway as a promising potential biomarker in synucleinopathies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107243"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846712","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":"Nerve injury promotes glial immune responses through a Draper/Ninjurin A pathway","authors":"Cole R. Brashaw ,&nbsp;Annie M. Griffin ,&nbsp;Sean D. Speese ,&nbsp;Mary A. Logan","doi":"10.1016/j.nbd.2025.107242","DOIUrl":"10.1016/j.nbd.2025.107242","url":null,"abstract":"<div><div>Degenerating neurons elicit striking immune reactions from glial cells, including directed invasion of injury sites and engulfment of neuronal debris. While these conserved glial immune responses are neuroprotective, our mechanistic understanding of glial immunity in the damaged and diseased brain is still incomplete. Here, using an in vivo nerve injury assay in the adult <em>Drosophila</em> olfactory system, we characterize a novel role for the transmembrane adhesion molecule Ninjurin A (NijA). We show that <em>NijA</em> is transcriptionally upregulated in neuropil ensheathing glia, but not local astrocytes, within hours after olfactory nerve transection. In <em>NijA</em> mutants, glia fail to properly infiltrate areas that contain severed olfactory nerves, and degenerating axonal debris is not cleared from the CNS. One well-defined signaling cascade critical for ensheathing glial clearance of damaged olfactory axons is the conserved MEGF10/Draper pathway, which includes the engulfment receptor Draper, downstream transcriptional regulators Stat92E and AP-1, and their known gene target <em>MMP-1</em>. We show that injury-induced transcription of <em>NijA</em> in responding glia requires the Draper receptor, but not Stat92E, AP-1, or MMP-1, suggesting a parallel signaling cascade activated downstream of Draper. Our findings reveal an essential role for the glial adhesion factor NijA in morphological and phagocytic responses to CNS damage, highlighting this conserved molecule as a new potential glial therapeutic target for neurodegenerative conditions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107242"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834358","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":"Nuclear ASC speck formation in microglia is associated with inflammasome priming and is exacerbated in LRRK2-G2019S Parkinson's disease","authors":"Luca Ballotto ,&nbsp;Thomas Baratta ,&nbsp;Helena Winterberg ,&nbsp;Cédric Dusanter ,&nbsp;Sara Sambin ,&nbsp;Jean Christophe Corvol ,&nbsp;Ludovica Iovino ,&nbsp;Luigi Bubacco ,&nbsp;Olga Corti ,&nbsp;Elisa Greggio ,&nbsp;Salvatore Novello","doi":"10.1016/j.nbd.2025.107237","DOIUrl":"10.1016/j.nbd.2025.107237","url":null,"abstract":"<div><div>Neuroinflammation is increasingly recognized as a central pathological mechanism in Parkinson's disease (PD), a progressive neurodegenerative disorder marked by dopaminergic neuron loss and diverse motor and non-motor symptoms. The NLRP3 inflammasome and its adaptor protein ASC are critical to initiating and sustaining inflammatory responses in the central nervous system. Although acute inflammasome activation supports host defence responses, chronic activation has been linked to the pathogenesis of PD. Increasing evidence indicates that mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2), particularly the PD-associated G2019S mutation, enhance inflammatory signalling in microglia and peripheral immune cells. However, how LRRK2 intersects with the NLRP3 pathway remains unclear. Here, we investigate the role of LRRK2-G2019S in the priming and activation of the inflammasome in mouse primary microglia and human monocyte-derived microglia-like cells (hMDMi). Under unstimulated conditions, LRRK2-G2019S microglia displayed elevated NLRP3 expression and spontaneous formation of ASC specks within the nucleus, a subcellular localization not previously reported in microglia. Nuclear ASC specks also emerged in Wild Type microglia and hMDMi after lipopolysaccharide priming, but progressed to cytosolic ASC specks and IL-1β release only after canonical activation of NLRP3. These findings suggest that nuclear ASC specks mark a primed state of inflammasome activation in microglia. The LRRK2-G2019S mutation enhances this phenotype, potentially predisposing microglia to exaggerated inflammatory responses. This work identifies a novel cellular feature associated with PD-linked LRRK2 and uncovers a previously unrecognized layer of inflammasome regulation in microglia, offering new avenues to understand and target neuroinflammation in PD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107237"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846695","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":"Diabetes increases SCO-spondin secretion but reduces Wnt5a interaction with ependymal cells, inducing ciliary stiffness and Frizzled-2 downregulation","authors":"Manuel Cifuentes ,&nbsp;Eder Ramírez ,&nbsp;María José Barahona ,&nbsp;Fernando Martínez ,&nbsp;Isabelle de Lima ,&nbsp;Luciano Ferrada ,&nbsp;Romina Bertinat ,&nbsp;Felipe Ávila ,&nbsp;Natalia Saldivia ,&nbsp;Margarita Pérez-Martín ,&nbsp;Begoña Oliver-Martin ,&nbsp;Nicolás Ciano-Petersen ,&nbsp;María del Mar Fernández-Arjona ,&nbsp;Katterine Salazar ,&nbsp;Francisco Nualart","doi":"10.1016/j.nbd.2025.107225","DOIUrl":"10.1016/j.nbd.2025.107225","url":null,"abstract":"<div><div>Diabetes is a chronic metabolic disorder with systemic complications. Hyperglycemia damages multiple organs, including the brain, increasing the risks of stroke, dementia, and oxidative stress. Diabetes is also linked to ventricular enlargement in the human brain. Here, we examine how diabetes alters the secretion of subcommissural organ spondin (SCO-spondin) and Wnt5a by SCO cells, which subsequently affects ependymal ciliary beating and cerebrospinal fluid (CSF) circulation. Under diabetic conditions, SCO-spondin secretion by SCO cells increased. CSF-borne SCO-spondin was observed interacting with ependymal cilia, which showed increased stiffness. Control SCO cells were Wnt5a-positive, indicating active biosynthesis and secretion; in contrast, Wnt5a immunostaining was negative under diabetic conditions, and its interaction with ependymal cells decreased. Additionally, the Wnt5a receptor Frizzled-2 and the proteoglycan testican, essential for Wnt5a–receptor engagement, were not detected in ependymal cells during diabetes. To further explore downstream changes, we examined aquaporin-4 (AQP4) in control and diabetic samples and found condition-dependent differences in its subcellular distribution within ependymal cells. Accordingly, peri-ependymal edema and periventricular lucency were observed. Conversely, GLUT1, MCT2, and Cx-43 remained unchanged, suggesting that diabetes selectively modifies specific ependymal properties. Proteomic analysis of CSF from diabetic patients confirmed the presence of spondin-1 and thrombospondins, which may replace SCO-spondin in humans. Overall, these findings support a model where increased SCO-spondin release and decreased Wnt5a-Frizzled-2–testican signaling in ependymal cells promote ciliary stiffening and periventricular edema in the diabetic brain.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107225"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145794189","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":"Memory-guided saccade latency as a potential biomarker for axial symptoms and freezing of gait in Parkinson's disease","authors":"Miao Wang ,&nbsp;Yifan Li ,&nbsp;Jiarui Yao ,&nbsp;Wuji Zhao ,&nbsp;Chunyu Yin ,&nbsp;Junru Wu ,&nbsp;Jiao Zhao ,&nbsp;Wei Wang ,&nbsp;Mingsha Zhang ,&nbsp;Zhenfu Wang ,&nbsp;Xi Yin ,&nbsp;Xuemei Li ,&nbsp;Zhongbao Gao","doi":"10.1016/j.nbd.2025.107238","DOIUrl":"10.1016/j.nbd.2025.107238","url":null,"abstract":"<div><h3>Background</h3><div>Freezing of gait (FOG), a debilitating axial symptom of Parkinson's disease (PD), lacks objective detection methods. While antisaccade (AS) latency prolongation correlates with FOG, the more complex memory-guided saccade (MGS), which requires multistage motor sequence integration (a proposed FOG mechanism), remains unexplored in FOG.</div></div><div><h3>Methods</h3><div>We assessed prosaccade (PS), AS, and MGS via infrared eye tracking in 75 PD patients (25 with FOG [PD-FOG], 50 without FOG [PD-nFOG]) and 75 healthy controls (HCs). The clinical assessments included the MDS-UPDRS III, the NFOG-Q, and cognitive/affective scales. Group differences were analyzed using appropriate comparative tests. Spearman's rank correlation was employed to examine associations between the saccade metrics and demographics/clinical features. Multivariate logistic regression was used to identify saccade metrics and demographics/clinical features associated with FOG.</div></div><div><h3>Results</h3><div>Compared to PD-nFOG patients and HCs, PD-FOG patients presented significantly prolonged MGS latency (<em>p</em> &lt; 0.001) but not PS or AS latency. MGS latency showed the strongest correlation with axial symptoms [ρ = 0.494, <em>p (FDR)</em> &lt; 0.01], remaining significant after adjusting for confounders (ρ = 0.262, <em>p</em> = 0.026). Multivariate logistic regression identified MGS latency [OR per SD increase = 4.814, 95 % CI: 1.457–15.910, <em>p (FDR)</em> = 0.044] and axial subscore [OR = 1.711, 95 % CI: 1.129–2.592, <em>p (FDR)</em> = 0.044] is associated with FOG. The MGS latency distinguished PD-FOG patients from PD-nFOG patients with high accuracy (AUC = 0.840, 95 % CI: 0.738–0.942; sensitivity/specificity = 84 % at the 407.5 ms cutoff). MGS latency was also correlated with NFOG-Q score in PD-FOG patients (ρ = 0.423, <em>p</em> = 0.035).</div></div><div><h3>Conclusions</h3><div>Prolonged MGS latency is an independent indicator associated with axial symptoms and FOG in PD patients, suggesting that saccade represents a promising noninvasive approach for indirect identification of FOG and reflection of its severity.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107238"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828029","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":"Spinal circuit mechanisms constrain therapeutic windows for ALS intervention: A computational modeling study","authors":"Beck Strohmer ,&nbsp;Kaitlyn Grosh ,&nbsp;Roser Montañana-Rosell ,&nbsp;Santiago Mora ,&nbsp;Jessica Ausborn ,&nbsp;Ilary Allodi","doi":"10.1016/j.nbd.2025.107253","DOIUrl":"10.1016/j.nbd.2025.107253","url":null,"abstract":"<div><div>Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive breakdown of neural circuits which leads to motoneuron death. Earlier work from our lab showed that dysregulation of inhibitory V1 interneurons precedes the degeneration of excitatory V2a interneurons and motoneurons and that stabilizing V1–motoneuron connections improved motor function and saved motoneurons in the SOD1^G93A ALS mouse model. However, the optimal timing for this intervention remains unclear. To address this, we developed a spiking neural network model of spinal locomotor circuits to simulate healthy and ALS-like conditions. By modeling changes in network connectivity and synaptic dynamics, we predict that V1 dysregulation induces an imbalance in motoneuron output which results in flexor-biased activity, leading to the disruption of flexor–extensor coordination, and potentially contributing to selective vulnerability of flexor motoneurons. Stabilizing V1 synapses preserved motor output even after motoneuron loss, suggesting that therapeutic benefit is possible into symptomatic stages. However, model predictions also highlighted that after sustained synaptic loss and the development of slower synaptic dynamics within the network, synaptic stabilization leads to maladaptive extensor-biased activity, suggesting that excitatory/inhibitory balance impacts treatment effectiveness. Finally, the model indicated that V1 stabilization could lead to rescue of the V2a excitatory interneurons, a finding that we were able to confirm experimentally in the SOD1^G93A ALS mouse model. By exploring different scenarios of synaptic loss and cell dysregulation during synaptic stabilization, our models provide a framework for predicting candidate time windows for spinal circuit interventions, which may guide future preclinical investigations.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107253"},"PeriodicalIF":5.6,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889744","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 effects of alcohol dependence on the CSF proteome in mice: Evidence for blood-brain barrier dysfunction and neuroinflammation","authors":"Natalie P. Turner ,&nbsp;Michal Bajo ,&nbsp;Amanda J. Roberts ,&nbsp;Marisa Roberto ,&nbsp;John R. Yates III","doi":"10.1016/j.nbd.2025.107254","DOIUrl":"10.1016/j.nbd.2025.107254","url":null,"abstract":"<div><div>Alcohol use disorder (AUD) represents a significant neurological health burden, yet the biological mechanisms underlying alcohol-induced brain pathology remain incompletely understood. Moreover, the molecular underpinnings of the transition from alcohol exposure to alcohol dependence are not well-characterized. We used mass spectrometry (MS)-based proteomics in a preliminary discovery study to compare cerebrospinal fluid (CSF) of alcohol-exposed Non-dependent (Non-dep) versus alcohol-dependent (Dep) mice that underwent the chronic intermittent ethanol (alcohol) – two-bottle choice (CIE-2 BCE) procedure and systemic anti-IL-6 Receptor antibody administration (<em>n</em> = 9; female = 5, male = 4). CSF samples from individual mice were processed for proteomic analysis and digested with trypsin overnight. Peptides were analyzed via data-independent acquisition (DIA)-MS and data were processed in DIA-NN at 1 % FDR. We identified 595 unique proteins across both groups, with 140 proteins differentially detected in CSF from Dep mice and 62 proteins specific to alcohol-exposed but Non-dep controls. The Dep-specific proteins revealed signatures of blood-brain barrier (BBB) disruption, neuroinflammation, cellular stress responses, and complement system activation. In contrast, Non-dep-specific proteins indicated preserved protective mechanisms including complement regulation, anti-inflammatory signaling, and neuronal calcium homeostasis. Ethanol-dependent-specific findings include MMP2, BIP, and to a lesser extent VE-cadherin (CDH5) and VCAM1, indicative of the beginnings of endothelial damage and BBB disruption, alongside established neuroinflammation markers GFAP, CHI3L1, and CX3CL1. This work provides novel preliminary protein-level evidence that alcohol exposure and alcohol dependence are dichotomous; despite the small sample size and limited power for moderate effect sizes, there appears to be a clear molecular transition from maintained protective mechanisms to vascular damage, BBB breakdown, and sustained neuroinflammation.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107254"},"PeriodicalIF":5.6,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889825","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":"Autophagy-related proteomics reveals lysosomal alterations linked to C19orf12 mutations and candidate biomarkers in MPAN patients' fibroblasts","authors":"Barbara Pakula ,&nbsp;Agata Wydrych ,&nbsp;Magdalena Lebiedzinska-Arciszewska ,&nbsp;Patrycja Jakubek-Olszewska ,&nbsp;Marta Skowrońska ,&nbsp;Iwona Kurkowska-Jastrzębska ,&nbsp;Justyna Janikiewicz ,&nbsp;Aneta M. Dobosz ,&nbsp;Emre Hakli ,&nbsp;Jędrzej Szymański ,&nbsp;Paolo Pinton ,&nbsp;Agnieszka Dobrzyń ,&nbsp;Werner J.H. Koopman ,&nbsp;Mariusz R. Wieckowski","doi":"10.1016/j.nbd.2025.107255","DOIUrl":"10.1016/j.nbd.2025.107255","url":null,"abstract":"<div><div>Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) is the third most common genetically-defined subtype of Neurodegeneration with Brain Iron Accumulation (NBIA), a group of rare, clinically heterogeneous disorders. The MPAN pathomechanism, including the link between <em>C19orf12</em> mutations, iron accumulation, and metabolic alterations, is still poorly understood. While earlier research pointed to impaired autophagy in MPAN, a comprehensive understanding remains elusive. Here, we investigated the autophagy-linked proteome in primary fibroblasts derived from 18 MPAN patients and identified distinct alterations in autophagy-related protein expression. Importantly, a subset of these proteomic changes showed significant associations with disease severity, highlighting their potential relevance as biomarkers of clinical progression. Functional analyses further revealed increased lysosomal acidification as the most consistently affected autophagy-related process in MPAN fibroblasts. Notably, both proteomic and functional alterations were associated with C19orf12 mutation zygosity, underscoring its modulatory role in disease-relevant cellular pathways.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107255"},"PeriodicalIF":5.6,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889774","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":"Genetic disruption of leucine rich repeat transmembrane protein 4 like 1 induces a pro-social behavioural phenotype in zebrafish","authors":"Courtney Hillman ,&nbsp;Giulia Petracco ,&nbsp;Barbara D. Fontana ,&nbsp;María Florencia Scaia ,&nbsp;Elisa Dalla-Vecchia ,&nbsp;Jon H. Wetton ,&nbsp;William H.J. Norton ,&nbsp;Matthew O. Parker ,&nbsp;Florian Reichmann","doi":"10.1016/j.nbd.2025.107251","DOIUrl":"10.1016/j.nbd.2025.107251","url":null,"abstract":"<div><h3>Background</h3><div>In humans, disruptions in social behaviour are characteristic of many neuropsychiatric disorders, where both genetic risk factors and synaptic dysfunctions can contribute to the phenotype. Among the genes implicated in synaptic regulation, the synaptic adhesion protein leucine-rich repeat transmembrane protein 4 (LRRTM4) has been identified as a key player in maintaining synaptic function and neuronal circuit integrity. However, the potential involvement of LRRTM4 in modulating social behaviour and its contribution to social deficits has yet to be explored.</div></div><div><h3>Methods</h3><div>In the current study, we used zebrafish to study how deficiency in <em>lrrtm4l1</em>, a zebrafish orthologue of <em>LRRTM4</em>, affects sociality. For this, the social behaviour of homozygous <em>lrrtm4l1</em>^{<em>−/−</em>} mutant zebrafish was analysed in multiple behavioural assays and the brain transcriptome of mutant animals was investigated by RNAseq.</div></div><div><h3>Results</h3><div>Mutant zebrafish displayed a pro-social phenotype in multiple behavioural assays. Groups of <em>lrrtm4l1</em>^−/− zebrafish formed more cohesive shoals and mutant individuals spent more time in the vicinity of conspecifics during a social interaction test. They were also less aggressive and in contrast to wild-type zebrafish did not differentiate in their interactions with known and unknown groups of fish. Neurotranscriptomic analysis revealed 560 differentially expressed genes including changes in glutamatergic neurotransmitter signalling, tryptophan-kynurenine metabolism and synaptic plasticity.</div></div><div><h3>Conclusion</h3><div>These findings suggest that <em>lrrtm4l1</em> is an important regulator of social behaviour in zebrafish. In a translational perspective, LRRTM4 is a promising potential therapeutic target that warrants further investigation in the framework of neuropsychiatric conditions characterized by major social impairments.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107251"},"PeriodicalIF":5.6,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850463","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 GABA controls fidelity of temporal cortical processing in Fragile X Syndrome","authors":"Victoria A. Wagner ,&nbsp;Ritika Thapa ,&nbsp;Anna O. Norman ,&nbsp;Alexandra Varallo ,&nbsp;Jordan Wimberly ,&nbsp;Maham Rais ,&nbsp;Dmytro Gerasymchuk ,&nbsp;Timo P. Piepponen ,&nbsp;Khaleel A. Razak ,&nbsp;Maija L. Castren ,&nbsp;Iryna M. Ethell","doi":"10.1016/j.nbd.2025.107233","DOIUrl":"10.1016/j.nbd.2025.107233","url":null,"abstract":"<div><div>Astrocytes control neural communications by influencing GABAergic transmission through uptake and synthesis of GABA. Impaired GABAergic signaling is thought to underlie cortical hyperexcitability in autism. Here we show that dysregulation of astrocyte GABA transport in Fragile X syndrome (FXS), a leading genetic cause of autism, contributes to circuit hyperexcitability. Human FXS astrocytes derived from patient-specific induced pluripotent stem cells and mouse <em>Fmr1</em> knockout (KO) astrocytes display a significant increase in levels of GABA and GABA-synthesizing enzyme GAD65/67. Our astrocyte-specific <em>Fmr1</em> KO (cKO) mouse model reveals reduced inhibitory connectivity and impaired cortical responses to sound. Abnormal GABA transport in cortical astrocytes contributes to impaired fidelity of temporal processing and abnormal behaviors in cKO mice. Blocking astrocyte GABA transport enables higher PV expression, improves EEG responses to frequency-modulated sound, and corrects aberrant exploratory behavior. Our findings suggest astrocyte GABA transport plays a key role in regulating cortical inhibition, and contributes to autism-associated phenotypes.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"219 ","pages":"Article 107233"},"PeriodicalIF":5.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145828061","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}