ACS Chemical Neuroscience最新文献

{"title":"Body Temperature and Discriminative Stimulus Effects of Nicotine and Menthol Aerosols in Male Rats: Role of α4β2 Nicotinic Acetylcholine Receptors","authors":"Tae In Eom,&nbsp;Pill-Kyu Jang,&nbsp;Jiyun Nam,&nbsp;Suji Kim,&nbsp;Bong Hyo Lee,&nbsp;Suchan Chang,&nbsp;Hye Jin Cha,&nbsp;Jaesuk Yun,&nbsp;Chae Ha Yang,&nbsp;Sooyeun Lee,&nbsp;Seong Shoon Yoon","doi":"10.1021/acschemneuro.6c00295","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00295","url":null,"abstract":"<p>Menthol,a prevalent additive intobacco and electroniccigaretteproducts, has been reported to interact with nicotine at both neuropharmacologicaland behavioral levels. Although menthol alone is not reinforcing,converging evidence suggests that it may modulate the pharmacologicaland behavioral effects of nicotine through nicotinic acetylcholinereceptor (nAChR) mechanisms. Using an inhalation-based rodent modelthat mimics human exposure to electronic nicotine delivery systems,we examined how menthol aerosol influences nicotine-induced hypothermia,discriminative stimulus effects, and the potential involvement ofα4β2* nAChRs in male rats. Plasma nicotine, cotinine,and trans-3′-hydroxycotinine (3′-OH-cotinine) concentrationswere also measured to assess pharmacokinetic interactions. Mentholaerosol prolonged and potentiated nicotine-induced hypothermia, andthis effect was attenuated by the α4β2* receptor antagonistdihydro-β-erythroidine (DHβE). In drug discrimination(DD) assays, coinhalation of menthol enhanced nicotine-appropriateresponding, suggesting facilitation of nicotine’s interoceptivestimulus properties. These effects were also attenuated by DHβE,consistent with involvement of α4β2* nAChR-mediated mechanisms.In addition, the behavioral effects were accompanied by alterationsin nicotine pharmacokinetics, including increased levels of nicotinemetabolites. Collectively, these findings suggest that menthol modulatesnicotine’s pharmacological and behavioral effects, potentiallythrough α4β2* nAChR-dependent mechanisms. By prolongingnicotine’s physiological and interoceptive effects, mentholmay increase the salience of nicotine-related cues during inhalationexposure. These interactions could contribute to enhanced abuse liabilityassociated with menthol-containing nicotine products, although furtherstudies are required to establish causal mechanisms. This study providesmechanistic insight into menthol–nicotine interactions andhighlights considerations relevant to mentholated e-cigarette products.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 17","pages":"3203–3216"},"PeriodicalIF":4.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148870531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic Characterization of NABi as a Selective Inhibitor of SOD1G93A Aggregation: Structural Basis and Therapeutic Implications for ALS","authors":"Min-Kyung Nam,&nbsp;Yeram Oh,&nbsp;Yemi Choi,&nbsp;Jieun Lee,&nbsp;Gi Heon Jeong,&nbsp;Sangjun Park,&nbsp;Seung-Ah Yoo,&nbsp;Moonseok Kim,&nbsp;Seongman Kang,&nbsp;Hyangshuk Rhim","doi":"10.1021/acschemneuro.5c00977","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00977","url":null,"abstract":"<p>Amyotrophic lateral sclerosis (ALS) is a devastatingneurodegenerativedisease characterized by the progressive loss of motor neurons, withfamilial ALS (fALS) frequently caused by mutations in Cu/Zn superoxidedismutase (SOD1). The G93A mutation, one of the most aggressive forms,promotes the formation of cytotoxic protein aggregates through cross-β-sheetstructures, leading to neuronal dysfunction and death. In this study,we investigated the therapeutic potential of NABi (natural Aβbinder and Aβ-aggregation inhibitor), a stable small engineeredprotein composed of the N-terminal 90 amino acids of SOD1, originallydeveloped to target amyloid-β aggregation in Alzheimer’sdisease. Given the shared β-sheet-rich aggregation mechanismsbetween amyloid-β and mutant SOD1 proteins, we hypothesizedthat NABi could serve as a dual-action therapeutic for both diseases.Through an integrated approach involving structural, biochemical,and cellular analyses, we demonstrate that NABi exhibits a 4-foldgreater binding affinity for SOD1^G93A compared to SOD1^WT, selectively targeting the mutant protein via specific hydrophobicinteractions. Structural modeling using AlphaFold2 reveals that theG93A mutation exposes hydrophobic residues that create an optimalbinding interface for NABi. Functionally, NABi effectively inhibitsSOD1^G93A aggregation, as demonstrated by filter trap assaysand immunofluorescence microscopy, while maintaining the protein ina soluble, nontoxic state. Importantly, coexpression of NABi reducesSOD1^G93A-induced cytotoxicity by approximately 4-fold,significantly enhancing neuronal survival. These findings establishNABi as a promising therapeutic candidate for SOD1^G93A-associatedfamilial ALS, demonstrating its capacity to selectively target pathologicalprotein conformations while preserving normal cellular function. Ourresults support the development of NABi as an innovative pan-therapeuticapproach targeting shared aggregation pathways across multiple neurodegenerativediseases.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 17","pages":"3156–3168"},"PeriodicalIF":4.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148861400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP13-SKP2-P57/kip2 Axis Mediates Spautin-1 Induced Transcriptional Upregulation of NURR1: Implications for NURR1 Mediated Neurotrophic Activity","authors":"Anna Edward,&nbsp;Srinivas N. Puttapaka,&nbsp;Aravind Vulli,&nbsp;Shasi V. Kalivendi","doi":"10.1021/acschemneuro.6c00485","DOIUrl":"10.1021/acschemneuro.6c00485","url":null,"abstract":"<p>The progressive loss of midbrain dopamine neurons leadingto motordeficits is the primary cause of Parkinson’s disease (PD).Emerging reports on the role of NURR1 in the differentiation and maintenanceof dopamine neurons; the association of reduced levels/familial mutantsof NURR1 in PD subjects makes it a promising candidate for developingnovel therapeutics. In the present study, while examining the effectsof known deubiquitinase inhibitors, we have identified that the USP10/13inhibitor, spautin-1, upregulated NURR1 levels in a transcription-dependentmanner. Further, USP13, but not USP10, was found to be essential inspautin-1-mediated NURR1 regulation. Reports indicate that USP13 deubiquitinatesSKP2 and thereby prevents it from degradation. Also, SKP2 is an E3ligase for P57/kip2 and reduced SKP2 expression leads to enhancedP57/kip2 levels. In line with the above findings, cells treated withspautin-1 exhibited reduced SKP2 with a concomitant increase in P57/kip2levels. Our results indicate that spautin-1-mediated regulation ofthe USP13-SKP2-P57/kip2 axis could play a crucial role in NURR1 upregulationsince overexpression of SKP2, or knockdown of P57/kip2, abrogatedspautin-1-mediated effects. Further, spautin-1 mediated neurite outgrowthof dopaminergic cells was mitigated under NURR1 knockdown conditions,indicating that small molecule activators of NURR1 could promote neuriteoutgrowth. Lastly, the ability of spautin-1 in enhancing tyrosinehydroxylase staining in vivo in PD mouse model suggests that pharmacologicalactivation of NURR1 could mitigate biochemical manifestations of PD.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 17","pages":"3239–3251"},"PeriodicalIF":4.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148756826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NLX-112, a Selective 5-HT1A Receptor Agonist, Upregulates GDNF and is Neuroprotective Against MPTP-Induced Nigrostriatal Degeneration in a Mouse Model of Parkinson’s Disease","authors":"William H. Powell,&nbsp;Lucy E. Annett,&nbsp;Ronan Depoortere,&nbsp;Adrian Newman-Tancredi,&nbsp;Mahmoud M. Iravani","doi":"10.1021/acschemneuro.6c00251","DOIUrl":"10.1021/acschemneuro.6c00251","url":null,"abstract":"<p>NLX-112 is a potent and selective 5-HT_1A agonistthathas successfully completed a Phase 2A clinical trial for the treatmentof L-DOPA-induced dyskinesia in Parkinson’s disease (PD) patients.Here, we investigated the neuroprotective activity of NLX-112 in amouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model ofPD. Four groups of male mice received subcutaneous administrationsof either saline (1 mL/kg) daily for 15 days, MPTP (21.4 mg/kg for5 days, preceded and followed by 5 days of saline, NLX-112 (1 mg/kg/dayfor 15 days), or combined MPTP + NLX-112. Two weeks following thecessation of treatments, mice treated with NLX-112 alone or NLX-112/MPTPshowed increased locomotor activity and reduced anxiety-like behavior(as assessed by a 40% reduction of thigmotaxis) in an open-field test,consistent with sustained effects of 5-HT_1A receptor activation.MPTP-treated mice showed a 40% reduction of dopaminergic (i.e., tyrosinehydroxylase immunoreactive; TH-ir) neurons in the substantia nigracompacta (SNc) and a 55% reduction of nerve terminals in the striatum.NLX-112 treatment completely prevented TH-ir neuron loss and reducedMPTP-induced dopamine nerve terminal loss to 30%. MPTP also markedlyincreased the levels of GFAP-ir astrocytes and Iba1-ir microglia inthe SN, as well as coexpression of glial-derived neurotrophic factor(GDNF) in the GFAP-ir astrocytes in both the SNc and the striatum.NLX-112 markedly reversed this MPTP-induced microglial overactivationin the SNc, and upregulated GFAP/GDNF colocalization in both the striatumand the SNc. Overall, the present study demonstrates a robust neuroprotectiveeffect of NLX-112 in a mouse model of PD by preventing microgliosis,upregulating GDNF, and favoring sustained pro-locomotor activity.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 17","pages":"3192–3202"},"PeriodicalIF":4.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148373662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Preclinical Evaluation of a Novel PET Probe for Phosphodiesterase 7B Imaging in Brain","authors":"Tomoteru Yamasaki,&nbsp;Zhiwei Xiao,&nbsp;Masayuki Fujinaga,&nbsp;Wakana Mori,&nbsp;Yiding Zhang,&nbsp;Jian Rong,&nbsp;Katsushi Kumata,&nbsp;Zhendong Song,&nbsp;Yusuke Kurihara,&nbsp;Haofeng Shi,&nbsp;Masanao Ogawa,&nbsp;Jiyun Sun,&nbsp;Nobuki Nengaki,&nbsp;Taoqian Zhao,&nbsp;Tomomi Kokufuta,&nbsp;Kazui Nakamoto,&nbsp;Lin Xie,&nbsp;Yinlong Li,&nbsp;Steven H Liang,&nbsp;Ming-Rong Zhang","doi":"10.1021/acschemneuro.6c00461","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00461","url":null,"abstract":"<p>Phosphodiesterase7B (PDE7B) is involved in the cAMP-PKA signalingpathway and has been implicated in neurodegenerative disorders. Accordingly,PDE7B represents a promising target for the development of therapeuticsto treat such diseases. Recent efforts have led to the discovery ofpyrimidinone-based compounds with high affinity and selectivity forPDE7B. In this study, we developed a novel pyrimidinone-based positronemission tomography (PET) probe, [¹¹C]<strong>5</strong>. <em>In vitro</em> autoradiography using rat brain sections revealedspecific binding of [¹¹C]<strong>5</strong> in the striatumand thalamus, consistent with the known distribution of PDE7B. BaselinePET scans showed relatively low brain uptake of [¹¹C]<strong>5</strong>, except in the olfactory bulb. Pretreatment with elacridar,a potent dual inhibitor of drug efflux transporters P-glycoprotein(P-gp) and breast cancer resistance protein (BCRP), enhanced the brainuptake of [¹¹C]<strong>5</strong>, resulting in further specific <em>in vivo</em> binding in the olfactory bulb and striatum. In conclusion,although the brain permeability of [¹¹C]<strong>5</strong> waslimited by P-gp and BCRP, [¹¹C]<strong>5</strong> demonstratedspecific binding to PDE7B, both <em>in vitro</em> and <em>in vivo</em>, supporting its potential utility for imaging PDE7Bin the central nervous system.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 17","pages":"3229–3238"},"PeriodicalIF":4.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148870435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nitrogen Doping Reduces the Neurotoxic Effects of Graphene Quantum Dots by Suppressing Proinflammatory and Oxidative Stress Pathways","authors":"Priyanka Tiwari,&nbsp;Gorantla Vikas Babu,&nbsp;Vikrant Rahi,&nbsp;Ravinder K. Kaundal,&nbsp;Sanjay Tiwari","doi":"10.1021/acschemneuro.6c00370","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00370","url":null,"abstract":"<p>Graphene quantum dots (GQDs) and their nitrogen-dopedcounterparts(N-GQDs) have recently been explored in the management of neurologicaldisorders. However, their biocompatibility remains questionable, particularlysubsequent to direct brain exposure. In this study, we investigatedthe neurotoxicity of GQDs and N-GQDs in neuroblastoma cells and healthymice. The change in the viability of SH-SY5Y cells was examined atdifferent doses of quantum dots. Later, these were injected into theanimals via the intracerebroventricular route, and neurobehavioraltests and biochemical assays were performed. Apart from histologicalexaminations, immunohistochemical staining of tissue sections wascarried out to assess impairment in brain function and delineate theunderlying mechanism. We noticed significantly higher cell death andneurobehavioral impairment in the presence of GQDs. Signs of oxidativestress and neuroinflammation were evident from the upregulation ofoxidative stress markers (GSH and MDA), inflammatory mediators (TNF-αand IL-1β), and glial activation. Neurotoxicity of GQDs couldfurther be confirmed from the data of Nissl’s, hematoxylinand eosin, and Luxol fast blue staining experiments. On the contrary,neuronal morphology of the hippocampal region and myelinated structureslooked well-preserved in N-GQD-treated animals. Altogether, we concludethat nitrogen-doped quantum dots could protect the animals againstdepletive neurobehavioral changes.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 17","pages":"3217–3228"},"PeriodicalIF":4.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148870403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein Aggregates as Drivers of Receptor Clustering and Pathological Signaling: A Framework Linking Extracellular Amyloid-β to Tau Dysregulation","authors":"Renan C. Ratis,&nbsp;Juliana S. Bonini,&nbsp;Angelica B. W. Bold","doi":"10.1021/acschemneuro.6c00331","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00331","url":null,"abstract":"<p>Extracellular protein aggregates have long been viewedprimarilyas toxic deposits, yet this framing fails to explain a critical clinicalobservation: removal of amyloid-β oligomers does not halt orreverse Alzheimer’s disease progression. Here, we propose thatthis paradox reflects the emergence of a self-sustaining intracellularsignaling state, initiated by aggregate-driven receptor clusteringbut capable of persisting independently of the original extracellulartrigger. We argue that oligomeric assemblies act as multivalent scaffoldsthat cross-link cell-surface receptors, inducing nanoscale clusteringand the formation of signaling-competent membrane platforms. In Alzheimer’sdisease, this mechanism links amyloid-β to a receptor complexinvolving PrP^c and mGluR5, leading to Fyn activation anddownstream tau hyperphosphorylation. Critically, redistributed tauenhances Fyn recruitment to postsynaptic compartments, establishinga positive feedback loop in which kinase activity and tau pathologybecome mutually reinforcing, and progressively decoupled from theinitiating amyloid signal. This self-amplifying circuit provides amechanistic basis for the limited efficacy of amyloid-targeted therapiesand reframes the therapeutic window problem in neurodegeneration.Beyond Alzheimer’s disease, we propose that clustering-drivenfeedback loops may represent a generalizable principle in proteinopathiesinvolving extracellular or membrane-associated aggregates─suchas α-synuclein─though the applicability of this principleappears to depend on whether the aggregating protein directly engagescell-surface receptor systems. This framework shifts the focus fromaggregate burden to membrane organization and feedback topology asdeterminants of disease progression, and identifies the tau–Fynfeedback loop as a candidate therapeutic target in proteinopathies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 17","pages":"3150–3155"},"PeriodicalIF":4.5,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148861402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bis(styryl)benzene Probes for Targeting Early-Stage Amyloid-β Aggregates in Alzheimer’s Disease","authors":"Citlali Gutíerrez,&nbsp;Marie Mina,&nbsp;Jusung An,&nbsp;Saumitra Bhowmik,&nbsp;Kerui Xu,&nbsp;Jennifer Salaiza,&nbsp;Katie Chen,&nbsp;Tarek El Sayed,&nbsp;Liviu M. Mirica","doi":"10.1021/acschemneuro.6c00429","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00429","url":null,"abstract":"<p>With the recent FDA approval of antibody-based therapeuticsforAlzheimer’s disease (AD), the need for diagnostic tools capableof detecting the disease at the earliest stages has become increasinglyurgent. Although small molecules offer advantages in terms of production,stability, and accessibility, no imaging agent currently enables reliabledetection of early-stage aggregates of the amyloid-β (Aβ)peptide, among the earliest biomarkers in AD progression. Herein,we report a series of bis(styryl)benzene (BSB) probes derived fromthe methoxy-X04 scaffold and a systematic structure–activityinvestigation examining how targeted molecular modifications, includinghydroxyl positioning, (Me)HN or (Me)₂N substitution, andincorporation of a 1,4-dimethyl-1,4,7-triazacyclononane (tacn) moiety,modulate Aβ binding, cytotoxicity, and brain uptake. These methoxy-X04analogues retain Aβ affinity while exhibiting markedly improvedcytotoxicity profiles and logD values consistent with in vivo applicability.Amyloid-β binding was evaluated using age-dependent in situstaining of 5xFAD mouse brain sections, supported by in vitro fluorescence-basedoligomer and fibril assays and in silico analyses that reveal tunableselectivity toward early versus late Aβ aggregates. In vivobrain uptake studies of BSB5 and Me₂tacnBSB5 further supportthe utility of these probes as modular Aβ-targeting fragmentsfor the development of early-stage AD imaging agents.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 16","pages":"3109–3121"},"PeriodicalIF":4.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TPEN, a Well-Known Zinc Chelator, Sequesters Attomolar-Buffered Cellular Cu(I) Through an Oxygen-Dependent Mechanism","authors":"Arielle Nabatilan,&nbsp;Elena Sergeeva,&nbsp;M. Thomas Morgan,&nbsp;Abigail H. Wright,&nbsp;Larry I. Benowitz,&nbsp;Paul A. Rosenberg,&nbsp;Christoph J. Fahrni","doi":"10.1021/acschemneuro.6c00249","DOIUrl":"https://doi.org/10.1021/acschemneuro.6c00249","url":null,"abstract":"<p>The metal ion chelatorTPEN is widely used to study the role ofmobile zinc in biology; however, its high affinity for other metalions raises questions about the specificity when interpreting biologicaleffects of TPEN. Using the Cu(I)-selective chelator PSP-2, we foundthat the chelation of copper, and not zinc, likely stimulates axonregeneration after optic nerve injury, thus challenging the previousviewpoint that dysregulation of mobile zinc contributes to regenerativefailure upon optic nerve damage. Spectroscopic and electrochemicalmeasurements revealed that TPEN sequesters subattomolar buffered Cu(I)through a novel redox-trapping mechanism, which was corroborated byfluorescence imaging studies with a Cu(I)-selective probe in livecells. These findings highlight the ambiguity of TPEN-induced biologicaleffects and identify PSP-2 as a versatile tool for dissecting therole of copper in biological processes.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 16","pages":"3070–3081"},"PeriodicalIF":4.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human iPSC-Derived Spinal Cord Organoids – The First Electrophysiological Assessment of Neuronal Maturation","authors":"Oleksandr Ievglevskyi,&nbsp;Denis Zosen,&nbsp;Jordi Requena Osete,&nbsp;Joel C. Glover,&nbsp;Ragnhild Elisabeth Paulsen,&nbsp;Srdjan Djurovic,&nbsp;Elena Kondratskaya","doi":"10.1021/acschemneuro.5c00823","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00823","url":null,"abstract":"<p>The spinal cord exhibits a complex cytoarchitecture andneuronalcircuitry organization that challenges in vitro replication of itsfunctional integrity. Here we employed a previously published protocolto generate spinal cord organoids (SCOs) from human-induced pluripotentstem cells (hiPSCs). We characterized phenotypic changes in functionalneuronal properties in SCO neurons at early developmental stages (15–32days in culture) using a quantitative electrophysiological approach.Using the whole-cell patch-clamp technique to evaluate electrophysiologicalproperties, we found that SCO neurons exhibited progressive maturation,as evidenced by hyperpolarized resting membrane potentials, increasedinward current amplitude, refined action potential kinetics, and theearly emergence of mature-type firing patterns. In particular, weshow that the spike frequency adaptation phenomenon, which prevailsin motor neurons, appears at early stages of SCO neuron development.Immunohistochemical assessment confirmed the expression of key transcriptionfactors in motor neurons (ISLET1 and HB9) and immature spinal interneurons(LHX1/5 and PAX2). Collectively, our findings demonstrate that neuronsin hiPSC-derived SCOs exhibit physiological differentiation, whichis important for using SCOs to investigate human spinal cord developmentand advance translational research in CNS disorders and cell replacementtherapies.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"17 16","pages":"3048–3057"},"PeriodicalIF":4.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148769846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}