Journal of Neuroscience最新文献

{"title":"The Epigenetic Reader PHF23 Is Required for Embryonic Neurogenesis.","authors":"Yue Wen, Ping He, Zongyao Huang, Chaoqiong Ding, Ting Zhang, Lanxin Zhang, Jianan Zheng, Mei Chen, Chong Chen, Yu Liu, Yuan Wang, Yan Zhang","doi":"10.1523/JNEUROSCI.2090-24.2025","DOIUrl":"10.1523/JNEUROSCI.2090-24.2025","url":null,"abstract":"<p><p>Epigenetic mechanisms are crucial in the tightly regulated process of neurogenesis from radial glial cells (RGCs) to intermediate progenitor cells (IPCs) to neurons during embryonic brain development. Plant homeodomain (PHD) finger proteins as important epigenetic readers are implicated in development and diseases, yet their roles in embryonic neurogenesis remain largely unexplored. In this study, we found different PHD finger proteins are differentially expressed along the neurogenesis trajectory. Among them, we investigated the function of PHF23 using mouse models, which is highly expressed in RGCs and IPCs, but not in neurons. Our findings demonstrate that PHF23 is essential for proper neurogenesis, and <i>Phf23</i> knock-out (<i>Phf2</i>3-KO) results in cortical developmental defects due to differentiation blockade of RGCs. Mechanistically, PHF23 bind with HDAC2, inhibiting its deacetylation activity on the active histone mark H3K27ac, thereby promoting the expression of neuronal differentiation pathway genes such as <i>Tcf4</i> and <i>Eya1</i> Overexpression of <i>Tcf4</i> rescues the differentiation defects of <i>Phf2</i>3-KO NSCs. These results establish PHF23 as a pivotal regulator of neurogenesis, indicating cell type-specific functions of PHD finger proteins.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12199542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188410","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}

{"title":"µ-Opioid Receptor Control of Glutamate/GABA Coreleasing SUM and VTA Projections to the Dentate Gyrus.","authors":"Daria Oleinichenko","doi":"10.1523/jneurosci.0095-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0095-25.2025","url":null,"abstract":"","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"67 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144488034","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":"Erratum: Bellocchio et al., \"Sustained G_q-Protein Signaling Disrupts Striatal Circuits via JNK\".","authors":"","doi":"10.1523/JNEUROSCI.0980-25.2025","DOIUrl":"10.1523/JNEUROSCI.0980-25.2025","url":null,"abstract":"","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12199540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235813","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}

{"title":"Phonological Representations of Auditory and Visual Speech in the Occipito-temporal Cortex and Beyond.","authors":"Alice Van Audenhaege, Stefania Mattioni, Filippo Cerpelloni, Remi Gau, Arnaud Szmalec, Olivier Collignon","doi":"10.1523/JNEUROSCI.1415-24.2025","DOIUrl":"10.1523/JNEUROSCI.1415-24.2025","url":null,"abstract":"<p><p>Speech is a multisensory signal that can be extracted from the voice and the lips. Previous studies suggested that occipital and temporal regions encode both auditory and visual speech features but their location and nature remain unclear. We characterized brain activity using fMRI (13 males and 11 females) to functionally and individually define bilateral fusiform face areas (FFA), the left word-selective ventral occipito-temporal cortex (word-VOTC), an audiovisual speech region in the left superior temporal sulcus (lSTS); and control regions in bilateral scene-selective parahippocampal place areas (PPA). In these regions, we performed multivariate pattern classification of corresponding phonemes (speech sounds) and visemes (lip movements). We observed that the word-VOTC and lSTS represent phonological information from both vision and sounds. The multisensory nature of phonological representations appeared selective to the word-VOTC, as we found viseme but not phoneme representation in adjacent FFA, while PPA did not encode phonology in any modality. Interestingly, cross-modal decoding revealed aligned phonological representations across the senses in lSTS, but not in word-VOTC. A whole-brain cross-modal searchlight analysis additionally revealed aligned audiovisual phonological representations in bilateral pSTS and left somato-motor cortex overlapping with oro-facial articulators. Altogether, our results demonstrate that auditory and visual phonology are represented in the word-VOTC, extending its functional coding beyond orthography. The geometries of auditory and visual representations do not align in the word-VOTC as they do in the STS and left somato-motor cortex, suggesting distinct representations across a distributed multisensory phonological network.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12199548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065066","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}

{"title":"Abrupt and Gradual Changes in Neuronal Processing upon Falling Asleep and Awakening.","authors":"Amit Marmelshtein, Barak Lavy, Barak Hadad, Yuval Nir","doi":"10.1523/JNEUROSCI.1288-24.2025","DOIUrl":"10.1523/JNEUROSCI.1288-24.2025","url":null,"abstract":"<p><p>The neural processes that change when falling asleep are only partially understood. At the cortical level, features of both spontaneous neural activity and sensory responses change between wakefulness and sleep. For example, in the early auditory cortex, sleep increases the occurrence of postonset silent (OFF) periods and elevates population synchrony. However, it remains unknown whether such changes occur abruptly or gradually around sleep onset and awakening. Here, we recorded spontaneous and sound-evoked neuronal spiking activity in the early auditory cortex along with polysomnography during thousands of episodes when male rats fell asleep or woke up. We found that when falling asleep, stimulus-induced neuronal silent periods (OFF periods), characteristic of nonrapid eye movement sleep, increased within a few seconds around sleep onset. In contrast, a gradual increase in neuronal population synchrony built up over tens of seconds until reaching maximal levels. EEG auditory-evoked potentials likely representing stimulus-triggered \"K-complexes\" changed along with postonset neuronal firing, whereas ongoing EEG slow-wave activity was associated with neuronal population synchrony. Similar effects, but with opposite direction, were observed around awakenings. The results highlight late stimulus-induced neuronal silence as a key feature changing abruptly around transitions between vigilance states, likely reflecting neuronal bistability and manifesting also in EEG-evoked potentials. More generally, these findings emphasize the added value of going beyond monitoring ongoing activity and perturbing the nervous system to reveal its state-an insight that could also help guide the development of more sensitive noninvasive monitors of falling asleep in humans.</p>","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12199541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188405","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}

{"title":"Purkinje cell spatial correlation dynamics are key to cerebellar cortical contributions to behavior.","authors":"Martha L Streng,Russell E Carter,Benjamin W Kottke,Kayla Togneri,Emma Wasserman,Vijay Rajendran,Suhasa B Kodandaramaiah,Esther Krook-Magnuson,Timothy J Ebner","doi":"10.1523/jneurosci.1915-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1915-24.2025","url":null,"abstract":"A major challenge in cerebellar physiology is determining how the stereotypic, conserved circuitry of the cerebellar cortex, with its dominant parasagittal and transverse architectures, underlies its fundamental computations and contributions to behavior. Recent advances have allowed for the resolution of Purkinje cell dendritic activity at large scales, but the full roles of these Purkinje cell dynamics during behavior remain undetermined. To interrogate Purkinje cell dynamics at the population level during behavior, we implemented a novel approach for awake, chronic, wide-field Ca2+ imaging of the cerebellar cortex. We performed wide-field cerebellar recordings in mice of both sexes exhibiting sparse expression of the Ca2+ indicator GCaMP6s, which importantly allowed for the resolution of both dendritic and somatic Purkinje cell activity. Blind source separation of wide-field dynamics using spatial independent component analysis (sICA) extracts components consisting of either Purkinje cell dendrites or somata, with distinct activity and spatial properties. These independent components (ICs) tend to be either parasagittally organized and likely reflective of dendritic activity, or more spatially distributed populations of Purkinje cell somata. We observe broad, bilateral activation of both these dendritic and somatic ICs during behavior, but they exhibit distinct and divergent patterns of spatial correlations occurring primarily along the parasagittal and transverse directions, consistent with the main geometry of the cerebellar cortex. Somatic correlation dynamics are robustly modulated by prediction errors and reflect ultimate behavioral outcomes. These results provide a novel link between cerebellar structure and function, with the correlation dynamics of Purkinje cell activity a key feature during behavior.Significance statement The cerebellar cortex exhibits highly conserved, elegant cytoarchitecture, but a full understanding of how this organization contributes to cerebellar processing is limited. We performed wide-field Ca2+ recordings of the primary output neurons of the cerebellar cortex, Purkinje cells, and find that they are organized into distinct networks, which are either parasagittally organized or distributed populations of somatic activity. While both networks are highly engaged during behavior, they exhibit distinct spatial correlation dynamics consistent with the main geometry of the cerebellar cortex, with somatic correlation dynamics conveying information about prediction error and behavioral outcomes. Together, these results provide new insights into the functional organization of Purkinje cells and implicate somatic network correlation dynamics as a key feature of cerebellar processing.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"639 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478674","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":"Emerging adulthood is marked by a cortical dendritic arborization phase depending on the actin nucleator Cobl.","authors":"Jule González Delgado,Katrin Pickrodt,Yuanyuan Ji,Sarah Krüger,Jana-Fabienne Rieß,Natja Haag,Britta Qualmann,Michael Manfred Kessels","doi":"10.1523/jneurosci.2062-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2062-24.2025","url":null,"abstract":"Puberty triggers significant changes. However, besides the pruning of synapses, little is known about more long-range alterations during brain maturation. Actin filament formation - a process ignited by actin nucleators - is crucial for life and also a driving force behind cellular morphology changes. Yet, the physiological importance of especially the more recently discovered, evolutionary younger actin nucleators largely remain elusive. We demonstrate the consequences of deficiency for the actin nucleator Cobl in the mouse brain. We identify remarkably layer- and age-restricted cortical Cobl KO phenotypes in dendritic arborization that first transiently emerge in layer V in rather young adolescent male mice and then manifested in a similar but more pronounced manner in layer II/III during the age of emerging adulthood. Cobl KO phenotypes were observed in the somatosensory cortex, prefrontal cortex and motor cortex. In WT mouse cortices, we discovered an increase in dendritic arbor complexity occurring during emerging adulthood and thereby identified a long-range process for cortical rewiring upon brain maturation. This dendritic arbor expansion is transient and largely erased during mature adulthood. The transient dendritic arbor expansion during emerging adulthood was accompanied by transient length changes of dendritic spines. Molecularly, the process thus seems to relate to alterations in actin dynamics. Importantly, both of these changes were completely absent in Cobl KO mice. Increased risk-taking of Cobl KO mice point towards a lack of maturity. These observations revealed the actin nucleator Cobl as first molecular component crucial for the identified emerging adulthood-related changes of neurons towards brain maturation.Significance statement Puberty triggers significant changes. We discovered a transient increase in dendritic arbor complexity occurring during emerging adulthood. This identified a long-range process for cortical rewiring during the age of emerging adulthood. Also dendritic spines were transiently rearranged. Both processes turned out to be dependent on the actin nucleator Cobl. We discovered remarkably layer- and age-specific cortical Cobl KO phenotypes in dendritic arborization. These first transiently emerged in layer V in adolescent mice and then manifested in a similar but more pronounced manner in layer II/III during the age of emerging adulthood. This identified the actin nucleator Cobl as the first crucial component for the discovered reorganizations towards brain maturation.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"9 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478680","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":"ALS mutations shift the isoelectric point of the KIF5A C-terminal inducing protein aggregation and TDP-43 mislocalization.","authors":"Pietro Zanella,Isabel Loss,Rosanna Parlato,Jochen H Weishaupt,Carlo Sala,Chiara Verpelli,Tobias M Boeckers,Alberto Catanese","doi":"10.1523/jneurosci.1658-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.1658-24.2025","url":null,"abstract":"Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by death of lower and upper motor neurons. Although the mechanism behind the selective neuron loss is still unclear, several heterogenous genes have been causally linked to ALS. KIF5A encodes for a neuronally enriched kinesin involved in protein transport and mutations within this gene have been causally linked to different motor neuron diseases. The mutations identified in ALS patients are mostly predicted to alter its mRNA splicing, leading to a frameshift mutation and an aberrant 39 amino acid-long sequence in the C-terminal domain of KIF5A.Here we found that ALS-related KIF5A mutations induce the accumulation of the mutant form of the protein in human motoneurons, which are also characterized by the cytosolic mislocalization of TDP-43. This ALS hallmark was even exacerbated upon overexpression of the ALS-KIF5A protein in cells differentiated from healthy controls and primary neurons, suggesting a pathological connection between the cellular load of the mutant protein and TDP-43 pathology. While the terminal domain of the WT isoform is characterized by an acid isoelectric point (pI), the ALS variant presents a basic pI due to the altered aminoacidic composition of this sequence. We thus generated a KIF5A ALS isoform that retained part of the aberrant sequence but with lower pI. The overexpression of this mutated variant led to significantly lower protein aggregation and TDP-43 mislocalization than the ALS mutant. Our data show that re-establishing the correct pI rescues KIFA aggregation and significantly reduces the cytoplasmic mislocalization of TDP-43.Significance Statement Amyotrophic Lateral Sclerosis is a lethal neurodegenerative disease to which no cure is still known. Heterogenous genes have been causally linked to ALS, yet, the exact pathomechanism responsible for neuronal death remains unclear. One such gene is KIF5A which encodes for a neuronally enriched kinesin. Identified mutations cause incorrect mRNA splicing resulting in an aberrant C-terminal aminoacidic sequence. Here, we identified TDP-43 cytosolic enrichment, a hallmark common to many ALS models, in two distinct hiPSC-derived motoneuron lines harboring the ALS mutation KIF5Ac2993-1 G>A Moreover, we generated a KIF5A isoform that retained most of the aberrant sequence but did not promote protein aggregation nor TDP-43 mislocalization upon overexpression. These results shed further light on the pathobiochemistry of the ALS-KIF5A cases.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"16 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478675","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":"Hearing loss and audiogenic seizures induced by hypofunctional prestin variants.","authors":"Satoe Takahashi,Yingjie Zhou,Frédéric Dépreux,Donna Whitlon,Mary Ann Cheatham,Kazuaki Homma","doi":"10.1523/jneurosci.0922-25.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.0922-25.2025","url":null,"abstract":"Prestin's voltage-driven motor activity confers sound-elicited somatic electromotility on auditory outer hair cells (OHCs) and is essential for the exquisite sensitivity and frequency selectivity of mammalian hearing. Lack of prestin results in ∼50 dB hearing threshold shifts across frequency, supporting the causal association of the prestin-coding gene, SLC26A5, with hereditary hearing loss, DFNB61. However, ∼50% reduction in prestin-mediated OHC electromotility barely affects cochlear function, and it is currently unknown how much electromotility is minimally required to support normal hearing. We generated mouse models harboring two deafness-associated prestin variants, p.A100T and p.P119S, and found that these missense variants do not deprive prestin of its fast motor function but significantly reduce membrane expression, leading to 70-80% reductions in OHC electromotility. Homozygous and compound heterozygous mice of either sex for these missense variants suffered congenital hearing loss; however, they still retained relatively low hearing thresholds at lower frequencies, pointing to the clinical possibility that a small augmentation of OHC electromotility could benefit those with DFNB61 hearing loss. These mice were also found to be prone to audiogenic seizures. This study thus provides insights into the minimum OHC electromotility required for normal cochlear operation and reveals the unappreciated importance of prestin for central gain control.Significance statement Prestin is abundantly expressed in the auditory outer hair cells and is essential for normal cochlear operation. Hence, reduction of prestin expression is often taken as indicative of reduced cochlear function in diseased or aged ears. However, this assumption overlooks the fact that cochlear function can tolerate surprisingly large reductions in prestin motor activity. DFNB61 mouse models generated and characterized in this study provide an opportunity to gauge the amount of prestin motor activity needed to sustain normal hearing sensitivity. This knowledge is crucial not only for understanding the pathogenic roles of deafness-associated variants that impair OHC electromotility but also for unraveling how prestin contributes to cochlear amplification.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"66 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478679","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 positive allosteric modulator of the SERCA pump rescues hippocampal neuronal circuits dysfunction and cognitive defects in a mouse model of Alzheimer's disease.","authors":"Evgenii Gerasimov,Anastasiya Rakovskaya,Ekaterina Pchitskaya,Olga Vlasova,Russell Dahl,Ilya Bezprozvanny","doi":"10.1523/jneurosci.2337-24.2025","DOIUrl":"https://doi.org/10.1523/jneurosci.2337-24.2025","url":null,"abstract":"Alzheimer's disease (AD) is a common neurodegenerative disorder that affects normal neuronal functioning, alters neuronal circuits activity and memory formation and storage. Disrupted neuronal calcium (Ca²⁺) signaling is one of the drivers of AD pathogenesis. Previously we suggested that positive allosteric modulators (PAMs) of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump may help to stabilize cytosolic Ca2+ levels and exert neuroprotective effects in AD neurons. In the current manuscript we demonstrate synaptoprotective properties of several SERCA PAMs using an in vitro model of amyloid toxicity. Based on in vitro experiments, we selected the SERCA PAM NDC-9009 for in vivo evaluation in male and female 5xFAD transgenic mice model of Alzheimer's disease. Using the miniscope imaging technique, we observed hyperactivity and abnormal connectivity of hippocampal neuronal ensembles 5xFAD mice. We further discovered that the function of the hippocampal neuronal circuits in 5xFAD mice was normalized by NDC-9009 intraperitoneal administration. NDC-9009 intraperitoneal administration also rescued memory defects in 5xFAD mice as quantified by the fear conditioning behavioral test and significantly reduced accumulation of amyloid plaques in hippocampal region of these mice. The obtained results support the potential utility of NDC-9009 and other SERCA PAMs as lead molecules for development of disease-modifying treatments for AD and potentially other neurodegenerative disorders.Significance statement Alzheimer's disease (AD) is a significant medical and social burden, yet no treatment currently exists. One of the hallmarks of AD is disrupted Ca²⁺ signaling, which contributes to neuronal dysfunction and degeneration. In the current study, we demonstrate the potential of the SERCA pump positive allosteric modulators (PAMs) as promising disease-modifying agents. Through an in vitro screening, we identified NDC-9009 as the most effective SERCA PAM, promoting robust cytosolic calcium clearance and exhibiting neuroprotective properties. Furthermore, using miniature fluorescence in vivo imaging, a significant restoration of hippocampal neuronal ensembles activity and cognitive function after chronic administration of NDC-9009 in the transgenic AD mouse model was demonstrated.","PeriodicalId":50114,"journal":{"name":"Journal of Neuroscience","volume":"58 1","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144478672","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}