eNeuro最新文献

{"title":"Dopamine Receptor 1 Specific CRISPRa Mice Exhibit Disrupted Behaviors and Striatal Baseline Cellular Activity.","authors":"Rianne R Campbell, Mikah Green, Eric Y Choi, Andreas B Wulff, Allison N Siclair, Smirti Khatri, Geralin Virata, Christina Barrett, Symphanie Key, Samir Patel, Mary Beth Rowell, Daniela Franco, Shanmugasundaram Ganapathy-Kanniappan, Brian N Mathur, Mary Kay Lobo","doi":"10.1523/ENEURO.0157-25.2025","DOIUrl":"10.1523/ENEURO.0157-25.2025","url":null,"abstract":"<p><p>The two main cell types in the striatum, dopamine receptor 1 and adenosine receptor 2a spiny projection neurons (D1-SPNs and A2A-SPNs), have distinct roles in regulating motor- and reward-related behaviors. Cre-selective CRISPR-dCas9 systems allow for cell-type specific, epigenomic-based manipulation of gene expression with gene-specific single guide RNAs (sgRNAs) and have potential to elucidate molecular mechanisms underlying striatal subtype mediated behaviors. Conditional transgenic Rosa26:LSL-dCas9-p300 mice were recently generated to allow for robust expression of dCas9-p300 expression with Cre-driven cell-type specificity. This system utilizes p300, a histone acetyltransferase which regulates gene expression by unwinding chromatin and making that region of the genome more accessible for transcription. Rosa26-LSL-dCas9-p300 mice were paired with Drd1-Cre and Ador2a-Cre mice to generate Drd1-Cre:dCas9-p300 and Ador2a-Cre:dCas9-p300 mouse lines and underwent behavioral phenotyping when sgRNAs were not present. Both Drd1-Cre:dCas9-p300 and Ador2a-Cre:dCas9-p300 have cell-type-specific expression of spCas9 mRNA. Baseline behavioral assessments revealed that, under a sgRNA absent nontargeted state, Drd1-Cre:dCas9-p300 mice display repetitive spinning behavior, hyperlocomotion, and enhanced acquisition of reward learning in comparison with all genotypic littermates. In contrast, Ador2a-Cre:dCas9-p300 do not exhibit any changes in behavior in comparison with their littermates. Electrophysiological recordings of dorsal striatum D1-SPNs revealed that Drd1-Cre:dCas9-p300 mice have increased input resistance and increased spontaneous excitatory postsynaptic current amplitude, together suggesting greater excitatory drive of D1-SPNs. Overall, these data demonstrate the necessity to validate CRISPR-dCas9 lines for research investigations. Additionally, the Drd1-Cre:dCas9-p300 line has the potential to be used to study underlying mechanisms of stereotypy and reward learning.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12360625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FiPhoPHA-A Fiber Photometry Python Package for Post Hoc Analysis.","authors":"Vasilios Drakopoulos, Alex Reichenbach, Romana Stark, Claire J Foldi, Philip Jean-Richard-Dit-Bressel, Zane B Andrews","doi":"10.1523/ENEURO.0221-25.2025","DOIUrl":"10.1523/ENEURO.0221-25.2025","url":null,"abstract":"<p><p>Fiber photometry is a neuroscience technique that can continuously monitor in vivo fluorescence to assess population neural activity or neuropeptide/transmitter release in freely behaving animals. Despite the widespread adoption of this technique, methods to statistically analyze data in an unbiased, objective, and easily adopted manner are lacking. Various pipelines for data analysis exist, but they are often system specific, are only for preprocessing data, and/or lack usability. Current post hoc statistical approaches involve inadvertently biased user-defined time-binned averages or area under the curve analysis. To date, no post hoc user-friendly tool with few assumptions for a standardized unbiased analysis exists, yet such a tool would improve reproducibility and statistical reliability for all users. Hence, we have developed a user-friendly post hoc statistical analysis package in Python that is easily downloaded and applied to data from any fiber photometry system. This Fiber Photometry Post Hoc Analysis (FiPhoPHA) package incorporates a variety of tools, a downsampler, bootstrapped confidence intervals (CIs) for analyzing peri-event signals between groups and compared with baseline, and permutation tests for comparing peri-event signals across comparison periods. We also include the ability to quickly and efficiently sort the data into mean time bins, if desired. This provides an open-source, user-friendly Python package for unbiased and standardized post hoc statistical analysis to improve reproducibility using data from any fiber photometry system.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Use of Internal States to Guide Behavior Is Associated with Functional Engagement of the Anterior Insula in Male Rats.","authors":"Mickaël Puaud, Dhaval D Joshi, Alfie Wright, Victor Ho, Aude Belin-Rauscent, Maxime Fouyssac, Barry J Everitt, Yvan Peterschmitt, David Belin","doi":"10.1523/ENEURO.0156-25.2025","DOIUrl":"10.1523/ENEURO.0156-25.2025","url":null,"abstract":"<p><p>Interoception and associated subjective states shape adaptive behaviors. In humans, interoceptive information is hierarchically processed in the insular cortex (IC), being integrated first in the posterior IC (PIC) and then processed in the anterior IC (AIC) to generate subjective states. However, it has not been established whether this is the case in other species nor whether utilization of interoceptive states to guide behavior is also specifically associated with functional engagement of the AIC, as suggested by this hierarchical model. We investigated in male Sprague Dawley rats whether the use of pharmacologically induced internal states to guide instrumental behavior in a discrimination task functionally engages the AIC as opposed to the mere experience of such states. Rats trained to use the interoceptive state produced by the centrally acting GABA_A receptor antagonist pentylenetetrazol (PTZ) or the peripherally acting β-adrenoreceptor agonist isoproterenol to guide their behavior performed as well in a discrimination task as those trained to use an exteroceptive visual discriminative stimulus. While interoceptive internal states were as potent as exteroceptive cues to guide instrumental behavior, only the former were associated with an increase in mRNA levels of the cellular plasticity marker, zif268 in the PIC, as assessed using qPCR. In contrast, zif268 mRNA levels increased in the AIC only after rats had used PTZ-induced interoceptive states to guide behavior, not simply in response to PTZ administration. These results show that in rats, the utilization of interoceptive states to guide behavior is associated with functional engagement of the AIC.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12345399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Speed of Visual Discrimination Differs between Foveola and Perifovea: A Combined EEG and Behavioral Investigation.","authors":"Alessandro Benedetto, Samantha K Jenks, Maruti V Mishra, Barry Giesbrecht, Martina Poletti","doi":"10.1523/ENEURO.0078-25.2025","DOIUrl":"10.1523/ENEURO.0078-25.2025","url":null,"abstract":"<p><p>Despite the vivid experience of homogeneous vision, our visual system is inherently endowed with highly inhomogeneous structures. Although the temporal characteristics of visual responses vary with eccentricity, the connection between this variation, the speed of visual processing, and its underlying neurophysiological mechanisms remains a topic of debate. Here, we performed simultaneous recordings of high-precision gaze positions and EEG activity to investigate how foveal and perifoveal stimulations impact reaction times (RTs) and visual evoked potentials (VEPs). Volunteers discriminated the position and orientation of a U-shaped figure with the aperture facing either upward or downward. Stimuli were presented briefly (50 ms) either in the foveola (0.33°) or perifovea (6.5°), to the right or left of the fixation point. Stimulus size in the perifovea condition was adjusted according to the cortical magnification factor (stimulus size: 0.2° and 0.75° for the foveola and perifovea conditions, respectively). When stimuli were equated for sensitivity and cortical area of stimulation, we observed faster RTs in the perifovea condition (16.8 ± 4 ms) compared to the foveola. The analysis of the VEP revealed a similar effect for the N1 response (11.0 ± 4 ms), a parieto-occipital component associated with discriminative processing and influenced by spatial attention. Overall, our findings suggest that visual discrimination speeds vary across eccentricities, with faster processing and shorter latency of early visual responses in the perifovea compared to the foveola.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12345403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered Cerebral Cortical Gyrification in Ferrets with Neonatal Exposure to the Bacterial Endotoxin, Lipopolysaccharide.","authors":"Kazuhiko Sawada, Rie Ryoke, Hiroi Nonaka, Ryuta Kawashima, Akira Sumiyoshi","doi":"10.1523/ENEURO.0135-25.2025","DOIUrl":"10.1523/ENEURO.0135-25.2025","url":null,"abstract":"<p><p>Lipopolysaccharide (LPS) is a bacterial endotoxin that induces innate immune responses. The present study aimed to elucidate alterations in cerebral cortical surface morphology induced by neonatal exposure to LPS using gyrencephalic ferrets. Male ferret pups received a subcutaneous injection of LPS (500 µg/g of body weight) on Postnatal Day (P)6 and P7. Furthermore, EdU and BrdU were administered on P5 and P7, respectively, to label postproliferative and proliferating cells that were exposed to LPS in the late stage of cortical neurogenesis. On P20 when the primary sulci and gyri had formed, MRI-based morphometry revealed an anterior shift in sulcal infolding in the medial and dorsolateral cortices of LPS-exposed ferrets. Immunofluorescence analysis showed that LPS increased the density of BrdU-labeled cells and reduced their apoptosis, as indicated by cleaved caspase-3 (cCasp3) immunostaining, in the outer stratum of the lateral sulcus located on the parietal association cortex. Furthermore, cCasp3 immunostaining of EdU-labeled cells was enhanced in the presylvian and lateral sulci located in the prefrontal and parietal association cortices, respectively, but was reduced in the coronal sulcus and gyrus located on the primary motor cortex in LPS-exposed ferrets. This study is the first to elucidate the effect of bacterial components on cerebral cortical sulcogyrogenesis, which is involved in the pathogenesis of neurodevelopmental disorders. Such altered sulcal topology may be attributed to a region-related effect on cortical neuron apoptosis in the medial and dorsolateral cortices caused by neonatal LPS exposure.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12331228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144689597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Subsecond Analysis of Locomotor Activity in Parkinsonian Mice.","authors":"Daniil Berezhnoi, Hiba Douja Chehade, Gabriel Simms, Liqiang Chen, Kishore Kumar S Narasimhan, Shashank M Dravid, Hong-Yuan Chu","doi":"10.1523/ENEURO.0014-25.2025","DOIUrl":"10.1523/ENEURO.0014-25.2025","url":null,"abstract":"<p><p>The degeneration of midbrain dopamine (DA) neurons disrupts the neural control of natural behavior, such as walking, posture, and gait in Parkinson's disease. While some aspects of motor symptoms can be managed by DA replacement therapies, others respond poorly. Recent advancements in machine learning-based technologies offer opportunities to better understand the organizing principles of behavior modules at fine timescales and its dependence on dopaminergic modulation. In the present study, we applied the motion sequencing (MoSeq) platform to study the spontaneous locomotor activities of neurotoxin and genetic mouse models of parkinsonism as the midbrain DA neurons progressively degenerate. We also evaluated the treatment efficacy of levodopa (l-DOPA) on behavioral modules at fine timescales. We revealed robust changes in the kinematics and usage of the behavioral modules that encode spontaneous locomotor activity. Further analysis demonstrates that fast behavioral modules with higher velocities were more vulnerable to loss of DA and preferentially affected at early stages of Parkinsonism. Last, l-DOPA effectively improved the velocity, but not the usage and transition probability, of behavioral modules in parkinsonian animals. In conclusion, the hypokinetic phenotypes in parkinsonism involve the decreased velocities of behavioral modules and their disrupted temporal organization during movement. Moreover, we showed that the therapeutic effect of l-DOPA is mainly mediated by its effect on the velocities of behavior modules at fine timescales. This work documents robust changes in the velocity, usage, and temporal organization of behavioral modules and their responsiveness to dopaminergic treatment under the parkinsonian state.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12333470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Excess Neonatal Testosterone Causes Male-Specific Social and Fear Memory Deficits in Wild-Type Mice.","authors":"Pravda Quiñones-Labernik, Kelsey L Blocklinger, Matthew R Bruce, Emily Hagan, Danielle Preuschl, Charlotte Tesar, Sarah L Ferri","doi":"10.1523/ENEURO.0020-25.2025","DOIUrl":"10.1523/ENEURO.0020-25.2025","url":null,"abstract":"<p><p>Neurodevelopmental disorders disproportionately affect males compared with females. The biological mechanisms of this male susceptibility or female protection have not been identified. There is evidence that fetal/neonatal gonadal hormones, which play a pivotal role in many aspects of development, may contribute. Here, we investigate the effects of excess testosterone (T) during a critical period of sex-specific brain organization on social approach and fear learning behaviors in C57BL/6J wild-type mice. Male, but not female, mice treated with T on the day of birth (Postnatal Day 0; PN0) exhibited decreased social approach as juveniles and decreased contextual fear memory as adults, compared with vehicle (veh)-treated controls. These deficits were not driven by anxiety-like behavior or changes in locomotion or body weight. Mice treated with the same dose of T on PN18, which is outside of the critical period of brain masculinization, did not demonstrate impairments compared with the veh group. These findings indicate that excess T during a critical period of early development, but not shortly after, induces long-term deficits relevant to the male sex bias in neurodevelopmental disorders.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Examining Relationships between Functional and Structural Brain Network Architecture, Age, and Attention Skills in Early Childhood.","authors":"Leanne Rokos, Signe L Bray, Josh Neudorf, Alexandria D Samson, Kelly Shen, Anthony R McIntosh","doi":"10.1523/ENEURO.0430-24.2025","DOIUrl":"10.1523/ENEURO.0430-24.2025","url":null,"abstract":"<p><p>Early childhood is a critical period showing experience-dependent changes in brain structure and function. The complex link between the structural connectivity (SC) and functional connectivity (FC) of the brain is of particular interest. However, its relationship with both age and attention in early childhood is not well understood. In this study, children between the ages of 4 and 7, and at a 1 year follow-up visit, underwent neuroimaging (diffusion-weighted and passive-viewing functional magnetic resonance imaging) and assessments for selective, sustained, and executive attention. We examined regional graph metrics and SC-FC coupling of the structural and functional networks. Partial least squares was used to investigate longitudinal brain measure changes and cross-sectional associations with age and attention. We observed longitudinal changes in functional graph metrics and age-related decreases in SC modularity. Region-wise graph analyses revealed variable brain-behavior relationships across the brain, highlighting regions where structural topology is linked to age and attentional performance. Furthermore, we identified SC as a dominant predictor of age when compared with FC and SC-FC coupling. The findings emphasize how early childhood is a dynamic period where cognitive functioning is intricately and predominantly linked to structural network features.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebellum Involvement in Visuo-vestibular Interaction for the Perception of Gravitational Direction: A Repetitive Transcranial Magnetic Stimulation Study.","authors":"Keisuke Tani, Hiroaki Tanaka, Akimasa Hirata, Yosuke Nagata, Nobuhiko Mori, Koichi Hosomi, Akiyoshi Matsugi","doi":"10.1523/ENEURO.0111-25.2025","DOIUrl":"10.1523/ENEURO.0111-25.2025","url":null,"abstract":"<p><p>Accurate perception of the direction of gravity relies on the integration of multisensory information, particularly from the visual and vestibular systems, within the brain. Although a recent study of patients with cerebellar degeneration suggested a cerebellar role in visuo-vestibular interaction in the perception of gravitational direction, direct evidence remains limited. To address this gap, we conducted two experiments with 42 healthy participants to evaluate the impact of repetitive 1 Hz transcranial magnetic stimulation (rTMS) over the posterior cerebellar vermis on visual dependency, quantified by the subjective visual vertical bias induced by rotating optokinetic stimulation (OKS). Electric field simulations in high-resolution generic head models were used to ensure focal stimulation of the cerebellum at the group level. The results demonstrated that the rTMS applied to the vermis significantly attenuated the OKS-induced shift in visual vertical (SVV) bias. This effect was not observed when stimulation was applied to the early visual cortex (V1-2) or the cerebellar hemisphere. Also, the vermis rTMS had no effect on the judgment precision in the absence of visual motion cues, suggesting that the rTMS may reduce visual weight in visuo-vestibular processing by increasing visual motion noise rather than affecting vestibular function. These findings suggest a direct involvement of the cerebellar vermis in the visuo-vestibular interaction underlying the perception of gravitational direction, providing new insights into cerebellar contributions in human spatial orientation.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Roles of the GPI-Anchor Cleaving Enzyme, GDE2, in Hippocampal Synaptic Morphology and Function.","authors":"Daniel Daudelin, Damani Sama-Borbon, Nan Zhang, Shanthini Sockanathan","doi":"10.1523/ENEURO.0102-25.2025","DOIUrl":"10.1523/ENEURO.0102-25.2025","url":null,"abstract":"<p><p>Hippocampal synaptic activity is tightly regulated to ensure appropriate synaptic function and plasticity, which are important for critical cognitive processes such as learning and memory. Altered hippocampal synaptic function can lead to cognitive and behavioral deficits observed in neurodegenerative diseases such as Alzheimer's disease (AD), necessitating a deeper fundamental understanding of hippocampal synaptic control mechanisms. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a surface transmembrane enzyme that cleaves the glycosylphosphatidylinositol anchor that tethers some proteins to the membrane. Mice lacking GDE2 (<i>Gde2</i>KO) display behavioral deficits in learning and memory that are hippocampal-dependent. However, roles of GDE2 in mouse hippocampal function are not known. Here, we show that GDE2 is expressed in pre- and postsynaptic compartments along apical dendrites in hippocampal CA1 cells. <i>Gde2</i>KO CA1 cells showed increased dendritic length and complexity and increased numbers of mushroom spines localized to the stratum radiatum. Furthermore, adult <i>Gde2</i>KOs displayed an increased frequency of miniature excitatory postsynaptic currents, impaired paired-pulse facilitation, and disrupted <i>N</i>-methyl-d-aspartate receptor (NMDAR)-mediated long-term depression (LTD). The phosphatidylinositol 3-kinase-AKT-glycogen synthase kinase 3 (PI3K-AKT-GSK3) signaling pathway, implicated in the inhibition of NMDAR-mediated LTD, was abnormally activated in the <i>Gde</i>2KO hippocampus, and inhibition of PI3K restored <i>Gde2</i>KO NMDAR-mediated LTD to WT levels. These observations identify GDE2 as an essential physiological regulator of CA1 synaptic morphology and hippocampal pre- and postsynaptic function, including the modulation of NMDAR-mediated LTD via the PI3K-AKT-GSK3 signaling axis.</p>","PeriodicalId":11617,"journal":{"name":"eNeuro","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}