Journal of Neurochemistry最新文献

{"title":"Preface to the Special Issue: “Molecular and Cellular Mechanisms of Memory”","authors":"Clara Ortega-de San Luis,&nbsp;Wayne S. Sossin","doi":"10.1111/jnc.70522","DOIUrl":"10.1111/jnc.70522","url":null,"abstract":"<p>A key question in neuroscience is how memories are formed and maintained at the molecular and cellular levels. Key findings on the importance of transcriptional and translational changes after an experience has occurred have not yet been transformed into a mechanistic understanding of how neuronal and synaptic properties encode the experience. In this special issue of the “Molecular and Cellular Mechanisms of Memory” we bring together 8 manuscripts that address this issue from a broad range of perspectives.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70522","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148447703","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":"Rethinking Alzheimer's Disease Therapy: From Amyloid-Centric Approaches to Multi-Target Phytochemical Strategies","authors":"Emre Aktaş,&nbsp;İlay Yurt,&nbsp;Yağmur Nisa Cerlet,&nbsp;Haşmet Ayhan Hanağası","doi":"10.1111/jnc.70506","DOIUrl":"10.1111/jnc.70506","url":null,"abstract":"<p>Alzheimer's disease (AD) is the leading cause of dementia, characterized by irreversible neuronal loss and progressive cognitive decline. The disease is driven by complex and interconnected pathological processes, including amyloid-β plaque deposition and tau neurofibrillary tangle formation, which converge on neuroinflammation, oxidative stress, synaptic dysfunction, and widespread neuronal network failure. Although recently approved antibody-based therapies such as lecanemab and donanemab effectively reduce cerebral amyloid burden, their clinical benefits remain modest and are accompanied by significant safety concerns, including amyloid-related imaging abnormalities (ARIA). Current pharmacological strategies predominantly rely on single-target mechanisms, an approach increasingly recognized as insufficient to address the multifactorial neurobiology of AD. This review critically evaluates the limitations of conventional amyloid-centric therapeutic strategies and contrasts them with emerging multi-target approaches based on phytochemicals. We synthesize current experimental and translational evidence to present a mechanistic framework illustrating how plant-derived bioactive compounds, including flavonoids and polyphenols, function as systems-level modulators of AD pathology rather than purely symptomatic agents. Particular emphasis is placed on their coordinated actions on amyloid processing via BACE1 inhibition, restoration of tau homeostasis through GSK-3β/PP2A regulation, attenuation of neuroinflammatory signaling, enhancement of endogenous antioxidant defenses through Nrf2 activation, and preservation of synaptic integrity. When considered collectively, the available evidence supports the concept that multi-target phytochemical strategies represent a biologically congruent and neurologically relevant paradigm for Alzheimer's disease therapy. Future progress will likely depend on integrating these compounds into broader polypharmacological and multidomain intervention frameworks, together with lifestyle-based strategies, repurposed drugs, anti-amyloid therapies, and rigorous translational validation.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70506","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148447688","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":"Caffeine Regulates GABA Transport Homeostasis in the Adolescent Mouse Frontal Cortex via Adenosine A1 Receptor and PKC-Dependent Pathways","authors":"Robertta Silva Martins,&nbsp;Vladimir Pedro Peralva Borges-Martins,&nbsp;Carlos Henrique de Carvalho Teixeira,&nbsp;Joana Gonçalves-Ribeiro,&nbsp;Sandra H. Vaz,&nbsp;Ricardo A. de Melo Reis,&nbsp;Ana M. Sebastião,&nbsp;Regina Célia Cussa Kubrusly","doi":"10.1111/jnc.70520","DOIUrl":"10.1111/jnc.70520","url":null,"abstract":"<div>\u0000 \u0000 <p>Adolescence is a period of several brain changes, making it especially vulnerable to external influences. Abuse of psychoactive drugs, such as caffeine (CAFF), generates changes in cognitive functions. The main pharmacological targets of CAFF are mainly the A₁R and A_2AR adenosine receptors, which can regulate GABA homeostasis. We therefore evaluated the influence of CAFF intake upon GABA uptake and release in the frontal cortex (FC) of adolescent Swiss mice and addressed the underlying mechanism. Mice were treated for 5 days with a subcutaneous injection of CAFF (10, 20, and 40 mg/kg) every 24 h, and the FC dissected out at 1 h after the last injection for measurement of [³H]-GABA uptake and release, cAMP accumulation, and density levels of GAT-1, A₁R, A_2AR, PKA, and PKC. Calcium (Ca²⁺) imaging was performed on primary neuronal cultures treated with CAFF (200 μM). CAFF increased [³H]-GABA uptake at all doses studied, an effect reversed by incubation with the selective GAT-1 uptake inhibitor, NO-711 (10 μM). At 20 and 40 mg/kg, CAFF also increased [³H]-GABA release. CAFF also increased A₁R, but not A_2AR levels. The influence of CAFF involves pPKC activity since CAFF enhanced the pPKC/PKC ratio, while the PKC-inhibitor Gö 6983 (100 nM) reversed the facilitatory action of CAFF upon GABA transport and prevented the CAFF-induced increase in the frequency of Ca²⁺ transients in neuronal cell cultures. We conclude that CAFF alters GABAergic homeostasis in the FC, increasing GABA transport through PKC-activity modulation.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148430708","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":"PBMC circRNA Profiles Distinguish Atypical From Idiopathic Parkinsonism and Track Clinical Severity Across Syndromes","authors":"Stylianos Ravanidis,&nbsp;Anastasia Bougea,&nbsp;Fedon-Giasin Kattan,&nbsp;Leonidas Stefanis,&nbsp;Epaminondas Doxakis","doi":"10.1111/jnc.70519","DOIUrl":"10.1111/jnc.70519","url":null,"abstract":"<p>Early separation of atypical Parkinsonian syndromes (APS) from idiopathic Parkinson's disease (iPD) remains challenging. Given that many brain-biased circular RNAs (circRNAs) are stable and expressed in blood cells, peripheral blood mononuclear cell (PBMC) circRNAs were profiled in 140 individuals (iPD 43, MSA 35, PSP 19, healthy controls 43) using RT-qPCR across 46 a priori candidates. Group differences were analyzed using the Kruskal–Wallis test with FDR correction; clinical associations were examined using Bonferroni-corrected Spearman correlations with a bootstrap stability assessment; and discrimination was assessed using logistic regression with nested repeated cross-validation, calibration analysis, and ROC analysis. Six circRNAs differed across groups after FDR adjustment (SLC8A1_circ_0000994, MAPK9_circ_0001566, MGA_circ_0000591, AGTPBP1_circ_0007162, SFMBT2_circ_0000211, HIPK3_circ_0000284), with median levels lowest in iPD and highest in PSP. Internally cross-validated multi-marker panels achieved AUCs of 0.88 for PSP versus controls, 0.78 for PSP versus iPD, and 0.67 for MSA versus iPD. Several circRNAs, including non-differential ones, showed bootstrap-stable associations with cognitive, mood, working-memory, and praxis measures. ENCORI- and CircInteractome-based analyses placed the differentially expressed circRNAs within a shared RBP interaction landscape and identified modest but significant miRNA-target overlap. Findings indicate that PBMC circRNA patterns aid APS-iPD differentiation and align with clinical impairment within this cohort; external validation, longitudinal assessment, and mechanistic studies are needed to establish diagnostic performance and biological relevance.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148404885","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":"From Synapses to Circuits, the Role of KIBRA and the WWC Family in Adaptive Brain Function","authors":"Lenora J. Volk","doi":"10.1111/jnc.70514","DOIUrl":"10.1111/jnc.70514","url":null,"abstract":"<p><i>KIBRA</i> (<i>WWC1</i>) has been a subject of scientific interest and investigation for almost two decades following its initial association with nonpathological variation in human memory performance. Work in a variety of animal models confirms that KIBRA supports memory function and demonstrates that regulation of AMPA-type glutamate receptors is a key mechanism by which KIBRA modulates neuronal function. KIBRA is a scaffolding protein at excitatory synapses, and its interactome is enriched for proteins that regulate AMPA receptor (AMPAR) trafficking and synaptic plasticity as well as neurodevelopmental disorders. Here, I provide a comprehensive discussion of known and potential mechanisms by which KIBRA and its interactome regulate adaptive brain function, encompassing AMPAR trafficking, synaptic plasticity, and experience-induced modification of circuit dynamics. Disrupted KIBRA function is implicated in a variety of cognitive disorders, and I review mechanisms by which KIBRA may contribute to neuropathology as well as recent work suggesting that KIBRA manipulation may be a target for cognitive enhancement. I expand the discussion to include recent data identifying the KIBRA homolog WWC2 as a regulator of GABA_A receptor expression at inhibitory synapses. In contrast to their distinct roles at excitatory and inhibitory synapses, KIBRA and WWC2 promote dendritic arborization in a non-redundant manner, and I discuss potential shared mechanisms by which WWC proteins regulate neuronal morphology as well as evidence that this function of WWC proteins may be disrupted in neurodevelopmental pathology.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70514","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396861","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 Golgi as a Microtubule Organiser in Neurons","authors":"Akila Yagoubat,&nbsp;Paul T. Conduit","doi":"10.1111/jnc.70511","DOIUrl":"10.1111/jnc.70511","url":null,"abstract":"<p>Microtubules are fundamental to neuronal architecture, providing the structural framework and transport tracks essential for polarisation, compartmentalisation and growth. While the centrosome is the canonical microtubule-organising centre (MTOC), neurons also rely on non-centrosomal MTOCs (ncMTOCs) as they mature. This review explores the emerging role of the Golgi apparatus as a key ncMTOC in both vertebrate and invertebrate neurons. We examine evidence that microtubule nucleation from the somatic Golgi supports initial polarisation and axon growth and regulates microtubule polarity. We also address the ongoing debate regarding Golgi outposts and their potential role in organising the dendritic microtubule network. By synthesising the available literature, we reconcile conflicting findings and identify gaps in our current understanding of Golgi-mediated nucleation and its role in organising the neuronal microtubule cytoskeleton.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70511","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148391042","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":"Exercise Snacking in Alzheimer's Disease: A Mechanistic Rationale Based on Repeated Exerkine Signaling","authors":"Ricardo A. L. De Sousa,&nbsp;Joyce Mirlane Moreira Costa,&nbsp;Ramona Ramalho de Souza Pereira,&nbsp;Leiriel Cristina dos Reis Vieira,&nbsp;Caíque Olegário Diniz e Magalhães,&nbsp;Marco Fabrício Dias-Peixoto","doi":"10.1111/jnc.70517","DOIUrl":"10.1111/jnc.70517","url":null,"abstract":"<p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70517","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382129","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":"Opposing Estrous Cycle-Dependent Norepinephrine and Dopamine Regulation in Response to Methamphetamine","authors":"Rohan V. Bhimani,&nbsp;Ryan C. Pauly,&nbsp;Elizabeth G. Mietlicki-Baase,&nbsp;Jinwoo Park","doi":"10.1111/jnc.70516","DOIUrl":"10.1111/jnc.70516","url":null,"abstract":"<div>\u0000 \u0000 <p>The central catecholamine systems, norepinephrine and dopamine, play a critical role in encoding the valence of environmental stimuli to promote engagement in behaviors that potentiate an organism's survival. Furthermore, both neurochemicals in limbic brain areas such as the nucleus accumbens (NAc) and bed nucleus of the stria terminalis (BNST) are major targets of stimulant drugs. Canonically, limbic norepinephrine signaling is enhanced in the presence of aversive or noxious stimuli whereas dopamine transmission is generally considered to increase in response to appetitive or rewarding stimuli. However, it remains to be elucidated whether sex differences, especially at different stages of the estrous cycle, distinctly regulate catecholamine transmission in vivo. In this study we (i) identified estrous cycle-dependent changes in catecholamine regulation via their transporters and autoreceptors in the BNST and NAc of anesthetized rats and (ii) determined how the psychostimulant methamphetamine (METH) impacts norepinephrine and dopamine transmission in the BNST and NAc, respectively, in male and freely cycling female rats using in vivo fast-scan cyclic voltammetry. Our results demonstrate electrically evoked BNST norepinephrine levels are increased by METH the greatest during the non-estrus (diestrus/proestrus) stages while NAc dopamine release evoked by electrical stimulation and METH is heightened in estrus. This limbic norepinephrine and dopamine regulation suggests a critical role of estrous cycle stage on catecholamine dynamics. These findings offer new insights into the role of estrous cycle stage on how the brain encodes environmental stimuli and provide a new framework for sex-specific therapies for targeting the central catecholamine systems in health and disease ranging from drug use disorders to obesity.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382178","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":"A PARK9 iPSC-Derived Dopaminergic Neuron Model Enables Drug Screening Targeting Autophagy-Lysosome Pathway Dysfunction in Parkinson's Disease","authors":"Kei-ichi Tsukiboshi,&nbsp;Kei-ichi Ishikawa,&nbsp;Akihiro Yamaguchi,&nbsp;Kimihito Arai,&nbsp;Kazuaki Kanai,&nbsp;Taiji Tsunemi,&nbsp;Hideyuki Okano,&nbsp;Nobutaka Hattori,&nbsp;Wado Akamatsu","doi":"10.1111/jnc.70515","DOIUrl":"10.1111/jnc.70515","url":null,"abstract":"<div>\u0000 \u0000 <p>Parkinson's disease (PD) is a neurodegenerative disease characterized by dopaminergic neuronal degeneration in the substantia nigra, in which lysosomal dysfunction and impaired autophagy–lysosome pathway activity are increasingly recognized as important pathogenic mechanisms. However, disease-modifying therapies targeting this pathway remain unavailable. Here, we generated induced pluripotent stem cells (iPSCs) from a PARK9 patient carrying an <i>ATP13A2</i> mutation and established mutation-corrected isogenic control iPSCs. PARK9 iPSC-derived neurons recapitulated lysosomal dysfunction–associated cellular phenotypes, including impaired lysosomal acidification, reduced mature cathepsin D levels, CD63-positive vesicle accumulation, LC3B-positive autophagosome accumulation, cytoplasmic pSer129 α-synuclein accumulation, and increased cleaved caspase-3 signals. These phenotypes were ameliorated in mutation-corrected neurons, supporting the contribution of ATP13A2 dysfunction to these abnormalities. We then performed high-content imaging–based compound screening targeting LC3B-positive autophagosome accumulation in PARK9 neurons. A three-step workflow identified 19 candidate compounds that reduced autophagosome accumulation consistent with partial improvement of lysosome-dependent downstream autophagosome processing rather than simple suppression of autophagosome formation. Among these, paroxetine, Ro 25-6981, amisulpride, and PK11195 showed additional, compound-dependent effects on PARK9-associated phenotypes, including lysosomal acidification, CD63-positive vesicle accumulation, cytoplasmic pSer129 α-synuclein signals, and cleaved caspase-3 signals. These findings establish PARK9 iPSC-derived neurons as a useful model of lysosomal dysfunction–associated PD pathology and provide a practical screening platform for identifying candidate compounds that modulate autophagy–lysosome pathway-related cellular phenotypes.</p>\u0000 <p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382161","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":"The Converging Effects of Different Categories of Antidepressants on the Brain: A Systematic Meta-Analysis of Public Transcriptional Profiling Data From the Hippocampus and Cortex","authors":"Eva M. Geoghegan,&nbsp;Megan H. Hagenauer,&nbsp;Erin Hernandez,&nbsp;Sophia Espinoza,&nbsp;Elizabeth I. Flandreau,&nbsp;Phi T. Nguyen,&nbsp;Adrienne N. Santiago,&nbsp;Mubashshir Ra’eed Bhuiyan,&nbsp;Sophie Mensch,&nbsp;Stanley J. Watson Jr.,&nbsp;Huda Akil,&nbsp;René Hen","doi":"10.1111/jnc.70502","DOIUrl":"10.1111/jnc.70502","url":null,"abstract":"<p>Depression can be treated with traditional pharmaceuticals targeting monoaminergic function, nontraditional drug classes and neuromodulatory interventions. To identify mechanisms of action shared across clinically-effective antidepressant treatment categories, we performed two systematic meta-analyses of public transcriptional profiling data from adult laboratory rodents (rats, mice). The outcome variable was gene expression, measured by microarray or RNA-Seq from bulk-dissected tissue from two depression-related brain regions (hippocampus, cortex). Relevant datasets were identified in the Gemma database of curated, reprocessed transcriptional profiling data using predefined search terms and inclusion/exclusion criteria (<i>hippocampus</i>: June 24, 2024, <i>cortex</i>: July 10, 2024). Differential expression results were extracted for all genes, minimizing bias. For each gene, a random effects meta-analysis model was fit to antidepressant vs. control effect sizes (Log2 Fold Changes) from each study for each brain region, with follow-up analyses exploring sources of effect heterogeneity. For the hippocampus, 15 relevant studies were identified, containing 22 antidepressant vs. control group comparisons (collective <i>n</i> = 313 samples), with approximately half representing traditional versus nontraditional antidepressants. Of 16 439 analyzed genes, 58 were consistently differentially expressed (False Discovery Rate (FDR) &lt; 0.05) following treatment. Antidepressant effects were enriched in the dentate gyrus and in gene sets related to stress regulation, brain growth and plasticity, vasculature and glia, and immune function. Comparisons with single nucleus RNA-Seq confirmed effects on specific hippocampal cell types, including potential rejuvenation of dentate granule neurons. For the cortex, 13 studies were identified, containing 16 antidepressant vs. control group comparisons (collective <i>n</i> = 233 samples). Of 15 583 analyzed genes, only one was consistently differentially expressed (FDR &lt; 0.05: <i>Atp6v1b2</i>), but overall expression patterns moderately resembled the hippocampus. These genes and pathways showing consistent differential expression across treatment categories may be promising targets for novel therapies. Future work should explore relevance to human clinical populations and potential heterogeneity introduced by sex and subregion.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 7","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70502","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376083","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}