Journal of Neurochemistry最新文献

{"title":"Embryonic Depletion of D-Aspartate Perturbs NMDA Receptor-Dependent Long-Term Potentiation in the Hippocampus of Juvenile Mice","authors":"Dalila Mango,&nbsp;Francesco Errico,&nbsp;Zoraide Motta,&nbsp;Sepideh Dashtiani,&nbsp;Anna Di Maio,&nbsp;Robert Nisticò,&nbsp;Maria Egle De Stefano,&nbsp;Loredano Pollegioni,&nbsp;Alessandro Usiello","doi":"10.1111/jnc.70566","DOIUrl":"10.1111/jnc.70566","url":null,"abstract":"<div>\u0000 \u0000 <p>D-Aspartate (D-Asp) is an endogenous NMDA receptor agonist that exhibits a pronounced developmental peak in the mammalian brain, suggesting a regulatory role in glutamatergic signaling and neurodevelopment. Disruption of D-Asp homeostasis has been associated with neuropsychiatric disorders characterized by early-life circuit vulnerability, including schizophrenia and autism spectrum disorders. However, its impact on hippocampal physiology remains incompletely defined. Here, we investigated how constitutive D-Asp depletion affects synaptic function in the hippocampal CA1 region of <i>Ddo</i>-knock-in (<i>Ddo</i>-KI) mice, in which zygotic overexpression of the D-Asp-degrading enzyme, D-aspartate oxidase (DDO or DASPO), results in embryonic and persistent D-Asp deficiency. Electrophysiological recordings were performed in acute hippocampal slices from male and female mice at postnatal Day 30 (P30) and Day 60 (P60). Analysis of basal synaptic transmission, assessed through paired-pulse ratio and spontaneous excitatory/inhibitory events, revealed no significant genotype-dependent differences. In contrast, NMDA receptor (NMDAR)-dependent synaptic plasticity was selectively altered, as theta-burst stimulation induced significantly greater long-term potentiation (LTP) in juvenile P30 <i>Ddo</i>-KI mice. This paradoxical enhancement was no longer observed at P60, indicating that the phenotype is developmentally restricted. Patch-clamp recordings further revealed a reduced AMPAR/NMDAR ratio in P30 <i>Ddo</i>-KI males, suggesting an altered balance between AMPAR- and NMDAR-mediated synaptic currents. Importantly, acute bath application of exogenous D-Asp rapidly restored LTP to wild-type levels, indicating that the electrophysiological phenotype is acutely reversible and sensitive to D-Asp availability. Biochemical analyzes confirmed increased DASPO activity and reduced D-Asp levels in <i>Ddo</i>-KI mice at both ages examined, indicating that the age-dependent plasticity phenotype is unlikely to result from age-dependent changes in D-Asp catabolism. Overall, these findings demonstrate that early developmental D-Asp deficiency induces a paradoxical, juvenile-specific enhancement of hippocampal NMDAR-dependent synaptic plasticity, highlighting the importance of D-Asp homeostasis during brain development.</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 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182539","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":"Increased Expression of α-Synuclein Impairs Trafficking of the Essential SNARE Protein Synaptobrevin-2","authors":"Elyas H. Arvell,&nbsp;James P. Carroll,&nbsp;Joshua Saito,&nbsp;Holly Melland,&nbsp;Ranjith R. Unnithan,&nbsp;Chris French,&nbsp;Danny M. Hatters,&nbsp;Sarah L. Gordon","doi":"10.1111/jnc.70568","DOIUrl":"10.1111/jnc.70568","url":null,"abstract":"<p>α-Synuclein is a presynaptic protein that has been extensively studied for its role in Parkinson's disease. Multiplication and missense variants in the gene encoding α-synuclein are causes of familial PD, and aggregated α-synuclein is a major component of Lewy bodies and Lewy neurites, the histopathological hallmark of the disease. However, the native function of α-synuclein remains unclear, though several lines of evidence suggest it modulates presynaptic function. α-Synuclein binds the vesicular SNARE protein synaptobrevin-2/VAMP2, and increased levels of α-synuclein potentiate SNARE complex levels without impacting exocytic rate. Given the essential role of synaptobrevin-2 in synaptic function we sought to examine how increased expression of α-synuclein, at levels observed in familial synucleinopathies with <i>SNCA</i> triplication, impacts the trafficking of this essential SNARE protein. Modest (approximately 2-fold) overexpression of α-synuclein in cultured murine hippocampal neurons caused a slowing in the endocytic retrieval of synaptobrevin-2, without impacting either the targeting of the protein to synapses or altering endocytosis. We also show that α-synuclein is not working antagonistically with the synaptobrevin-2 chaperone synaptophysin, and likely acts at least partially via direct binding to synaptobrevin-2. Finally, increased expression of α-synuclein induces synaptic depression upon repeated neuronal depolarisation, in a manner requiring binding to synaptobrevin-2. We reveal α-synuclein as a modulator of synaptobrevin-2 endocytic trafficking and highlight perturbed SNARE protein trafficking as a potential contributor to synaptic dysfunction and neuronal health in Parkinson's disease.</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 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70568","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137024","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":"Synaptic Proteostasis in Health and Disease","authors":"Paul G. Donlin-Asp,&nbsp;Emma L. Clayton","doi":"10.1111/jnc.70565","DOIUrl":"10.1111/jnc.70565","url":null,"abstract":"<p>Neurons rely on tightly coordinated mechanisms of protein synthesis and degradation to maintain cellular homeostasis, a process known as proteostasis. Given their highly polarised and compartmentalised nature, regulation of proteostasis is especially important at neuronal synapses, which are spatially distant from the soma yet require rapid on-demand adaptation of the synaptic proteome. Neurons meet their demand for synaptic proteostasis through localised mRNA transport and translation, alongside specialised pathways for protein degradation. Recent advances reveal that thousands of transcripts localise to distal neuronal compartments and that their distribution may be shaped by RNA stability, RNA dynamics, and organelle-hitchhiking transport mechanisms. In parallel, processes such as synaptic autophagy and endolysosomal trafficking are crucial for maintaining synaptic structure and neurotransmission. Disruptions in these finely balanced mechanisms are a common underlying feature of various neurological disorders, including fragile X syndrome, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. This overview highlights key milestones and remaining questions in synaptic proteostasis, focusing on how local protein synthesis and degradation work together to preserve synaptic integrity and how their dysregulation can lead to disease.</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 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70565","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136990","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":"Subtype-Specific Tubulin Post-Translational Modification Profiles Predict Differential Axonal Stability in DRG Neurons","authors":"Gil Song,&nbsp;Eun Mo Yang,&nbsp;Harryn Choi,&nbsp;Eun-Hae Jang,&nbsp;Jaeyong Kim,&nbsp;Hyuk-Joo Jeon,&nbsp;Eun-Mi Hur","doi":"10.1111/jnc.70564","DOIUrl":"https://doi.org/10.1111/jnc.70564","url":null,"abstract":"<div>\u0000 \u0000 <p>Sensory neurons of the dorsal root ganglia (DRG) comprise a heterogeneous population that transduces diverse somatosensory modalities, including proprioception, mechanosensation, thermosensation, and nociception. Although sensory neuron subtypes differ in function and transcriptional profiles, whether these neurons also differ in axonal microtubule properties remains unclear. Here, we asked whether distinct DRG neuronal subtypes exhibit subtype-specific axonal tubulin post-translational modifications (PTMs), which have been implicated in regulating microtubule structure and function. Using established markers, we resolved five major sensory neuronal subtypes in primary cultures of adult mouse DRG neurons: parvalbumin-positive (PV⁺) proprioceptors, Aβ low-threshold mechanoreceptors (LTMRs), calcitonin gene-related peptide-positive (CGRP⁺) peptidergic nociceptors, isolectin B4-positive (IB4⁺) non-peptidergic nociceptors, and tyrosine hydroxylase-positive (TH⁺) C-LTMRs. Axons exhibited subtype-specific differences in βIII-tubulin content and distinct tubulin PTM signatures, which were validated in vivo<i>.</i> CGRP⁺ and IB4⁺ neurons displayed lower levels of tubulin acetylation and glutamylation compared to PV⁺ neurons and LTMRs in both culture and tissue, and nociceptor neurons showed greater susceptibility to nocodazole-induced microtubule destabilization compared to PV⁺ neurons. Inhibition of histone deacetylase 6 conferred nocodazole resistance to both CGRP⁺ and IB4⁺ neurons. Together, these findings suggest that distinct tubulin PTM signatures contribute to axonal stability and vulnerability across sensory neuron subtypes and support the use of primary adult DRG neuron culture as a tractable platform for biochemical and functional dissection of sensory neuron populations.</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 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149099465","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":"Different Routes to Brain Resilience: Sex-Dependent Glial and Metabolic Adaptations","authors":"Meng-Yao Wang,&nbsp;Alicia Pellitero,&nbsp;Alberto Pérez-Samartín,&nbsp;Yong Tang,&nbsp;Carlos Matute","doi":"10.1111/jnc.70567","DOIUrl":"https://doi.org/10.1111/jnc.70567","url":null,"abstract":"&lt;p&gt;Brain resilience is the capacity to maintain or restore neural function when the nervous system encounters aging, metabolic stress, inflammation, or disease. It is often assessed by the extent of injury or loss of function, yet a similar outcome can emerge from different cellular responses. Resilience may depend less on maximal energy production than on metabolic flexibility: the capacity to adjust substrate use, energy generation, biosynthesis, and redox balance as demands change. Glia are well placed to coordinate these adjustments. Lesion-remote astrocytes, for example, promote microglia-mediated white matter repair through CCN1-dependent regulation of microglial lipid metabolism (McCallum et al. &lt;span&gt;2025&lt;/span&gt;). This interaction shows that metabolism in one glial population can influence the reparative activity of another. It also raises a broader question: if two brains preserve similar function after challenge, must they have used the same metabolic route?&lt;/p&gt;&lt;p&gt;We propose that biological sex may influence the relative recruitment of glial-metabolic pathways, without necessarily determining a single superior form of resilience. Single-cell analysis finds prominent sex-associated expression differences among glial populations (DeCasien et al. &lt;span&gt;2026&lt;/span&gt;), and sex-linked mechanisms can alter age- and Alzheimer's disease-related demyelination (Lopez-Lee et al. &lt;span&gt;2024&lt;/span&gt;). Adult microglia also retain sex-specific transcriptional features (Villa et al. &lt;span&gt;2018&lt;/span&gt;). Sex chromosomes, gonadal factors, and their interactions may therefore shape the cellular repertoire available during challenge. However, transcriptional differences do not by themselves reveal how substrates move between cells, whether a pathway is protective, or whether neural function is preserved. These distinctions are central to a metabolic account of resilience. They also require separating biological sex from social or environmental exposures, which can alter metabolic demand and are often unevenly distributed in human cohorts.&lt;/p&gt;&lt;p&gt;Astrocytes illustrate how the same type of challenge can engage different metabolic responses. They link neuronal activity to glucose uptake, glycogen turnover, lactate production, and purinergic signaling. In primary hypothalamic astrocytes, glucoprivation elicits sex-dependent regulation of glycogen metabolism involving estrogen receptors and AMPK signaling (Ibrahim et al. &lt;span&gt;2020&lt;/span&gt;). In a separate model, early-life stress recruits astrocytic ATP-related purinergic mechanisms more prominently in males and lactate-associated mechanisms more conspicuously in females (Depaauw-Holt et al. &lt;span&gt;2025&lt;/span&gt;). The experimental contexts differ, so these results should not be combined into a universal male or female metabolic program. They do show that the substrate and signaling pathways engaged by astrocytes can vary with sex. Whether these differences sustain comparable circuit performance under the same challenge ","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70567","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149099466","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":"Dual Roles of p53-Related Protein Kinase in Cytoskeletal Remodeling and Translational Control","authors":"Emiliano Molina,&nbsp;David Villarroel-Campos,&nbsp;Manuel Muñoz,&nbsp;Álvaro Glavic,&nbsp;Christian Gonzalez-Billault","doi":"10.1111/jnc.70562","DOIUrl":"https://doi.org/10.1111/jnc.70562","url":null,"abstract":"<p>P53-related protein kinase (PRPK; TP53RK) is an evolutionarily conserved atypical kinase whose biology reveals an unexpected integration of translational control, cytoskeletal regulation, and cell-type-specific stress responses. As a core component of the TCTC complex (<span>T</span>hreonyl-<span>C</span>arbamoyl <span>T</span>ransferase <span>C</span>omplex), PRPK participates in the universally conserved synthesis of the tRNA modification t⁶A, an essential process for translational fidelity, proteostasis, and cellular viability. Structural and biochemical studies from yeast to humans highlight a deeply conserved ATPase-driven mechanism in which PRPK undergoes conformational rearrangements to activate the catalytic subunit Tcs3, thereby coordinating tRNA positioning. Beyond this canonical role, PRPK displays additional functions. In <i>Drosophila</i> and mammalian systems, PRPK engages cytoskeletal regulators, including Rab35 and Arp2/3 subunits, to influence actin organization, neuronal polarity, and cell migration. These interactions suggest a second, TCTC-independent functional module through which PRPK integrates signaling pathways such as AKT and TOPK to shape cell survival, axon specification, and tumor progression. Dysregulation of PRPK in human disease further underscores its pleiotropy, as gain-of-function mechanisms promote oncogenesis and metastasis. In contrast, loss-of-function mutations in PRPK or other TCTC components cause Galloway–Mowat syndrome, characterized by microcephaly, nephrotic syndrome, and profound defects in proteostasis and cytoskeletal integrity. This Perspective synthesizes emerging concepts of PRPK as a dual-role regulator, acting in tRNA biology as well as in cytoskeletal and stress responses. We delineate unresolved questions regarding substrate identity, structural regulation, cell-type specificity, and the feasibility of selectively targeting PRPK for therapeutic purposes. Taken together, these findings reveal the richness and complexity of PRPK functions as a molecular regulator of translation, signaling, and cytoskeletal dynamics that are evolutionarily and mechanistically intertwined.</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 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70562","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149099464","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":"AMPK Activator MK-8722 Improves Spatial Memory Deficit and Alters Metabolome in APP/PS1 AD Mouse Model","authors":"Noelle I. Nicol,&nbsp;Tian Li,&nbsp;Qiang Su,&nbsp;Amelia Suhocki,&nbsp;Erin Dunlap,&nbsp;Xueyan Zhou,&nbsp;Hannah M. Jester,&nbsp;Nathaniel A. Swift,&nbsp;Ethan Underwood,&nbsp;Jingyun Lee,&nbsp;Rita Cervera-Juanes,&nbsp;Tao Ma","doi":"10.1111/jnc.70563","DOIUrl":"https://doi.org/10.1111/jnc.70563","url":null,"abstract":"<div>\u0000 \u0000 <p>Alzheimer's disease (AD) involves early synaptic vulnerability and systemic metabolic dysfunction, yet the impact of peripheral metabolic state on brain function remains unclear. Previous studies indicate a link between AMP-activated protein kinase (AMPK) signaling dysregulation and AD pathophysiology. Here we tested whether systemic treatment of a potent pan-AMPK activator MK-8722 influences cognitive function, synaptic plasticity, and circulating metabolic profiles in APP/PS1 AD model mice at the age of 6–8 months. MK-8722 was well tolerated and activated AMPK in the liver but not in the hippocampus. Our findings revealed that MK-8722 selectively improved AD-associated hippocampal-dependent spatial memory deficits and enhanced dendritic spine maturation in the hippocampus of APP/PS1 mice. In contrast, MK-8722 did not alter hippocampal long-term potentiation (LTP). In-depth analysis of plasma lipidomics and metabolomics revealed coordinated disruptions in glycerophosphatidylcholine species, glutathione cycling, carnitine-dependent fatty acid transport, and the kynurenine pathway in APP/PS1 mice, which were partially normalized by MK-8722 treatment. These findings suggest that peripheral AMPK activation can remodel systemic metabolic networks and improve certain aspects of cognitive and synaptic outcomes in early AD, supporting a model in which metabolic interventions outside the brain influence neuronal resilience.</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 10","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149099307","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":"Adolescent Exposure to a THC-Rich Cannabis Extract Produces Genotype-Dependent Effects on Cognition and Glial Morphology in Serine Racemase Mutant Mice","authors":"Igor F. Rangel,&nbsp;Melissa Chaves,&nbsp;Iohanna Pagnoncelli,&nbsp;Isabelle Medeiros,&nbsp;Felipe Pinheiro,&nbsp;Lorena Fortuna,&nbsp;Luiza Castello-Branco,&nbsp;Ernesto Diaz Roch,&nbsp;Virgínia Martins Carvalho,&nbsp;Flavia Regina Souza Lima,&nbsp;Rogério Panizzutti,&nbsp;Luciana Romão","doi":"10.1111/jnc.70559","DOIUrl":"10.1111/jnc.70559","url":null,"abstract":"<p>Adolescent cannabis exposure has been associated with an increased risk of schizophrenia; however, how genetic vulnerability shapes the long-term consequences of adolescent cannabinoid exposure remains poorly understood. Δ⁹-Tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis and the predominant cannabinoid in the THC-rich cannabis extract used here, primarily activates cannabinoid type 1 receptors (CB1). In parallel, reduced availability of D-serine, an endogenous co-agonist of N-methyl-D-aspartate receptors (NMDARs), has been implicated in the pathophysiology of schizophrenia. Here, we investigated whether adolescent exposure to a THC-rich cannabis extract modulated long-term behavioral, neurochemical, and glial outcomes in serine racemase mutant (SrrY269*) mice, a genetic model characterized by reduced D-serine levels and schizophrenia-relevant phenotypes. Mice received escalating oral doses of the THC-rich cannabis extract during adolescence and were evaluated in adulthood using behavioral assays, amino acid quantification, and glial morphometric analyses. Adolescent exposure to the THC-rich cannabis extract prevented deficits in prepulse inhibition and spatial object recognition memory in adult SrrY269* mice, while transiently impairing sensorimotor gating in wild-type animals. Irrespective of genotype, mice exposed to the THC-rich cannabis extract spent more time in the center of the open field in adulthood. In behaviorally tested SrrY269* mice, reduced hippocampal microglial branching was attenuated following adolescent treatment. In an independent behavior-naïve cohort, SrrY269* mice exhibited marked astrocytic morphological alterations, several of which were also attenuated by adolescent exposure to the THC-rich cannabis extract. In contrast, the same treatment induced a distinct astrocytic phenotype in wild-type mice. Adolescent exposure to the THC-rich cannabis extract did not alter hippocampal or prefrontal cortical levels of D-serine or other amino acids involved in NMDAR signaling in adulthood. These findings indicate that adolescent exposure to a THC-rich cannabis extract produces genotype-dependent long-term effects, preventing specific behavioral deficits and attenuating independently assessed microglial and astrocytic alterations in SrrY269* mice, while producing adverse behavioral and astrocytic outcomes in wild-type animals. Genetic background may therefore be an important determinant of the long-term neurodevelopmental consequences of adolescent exposure to THC-rich cannabis extracts.</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 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70559","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039292","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":"Chronic Methamphetamine Administration Increases Mitochondrial Density and Impairs Mitochondrial Function in the Substantia Nigra Pars Compacta","authors":"Aishwarya Bhowmik,&nbsp;Jennifer A. Wilking,&nbsp;Duha Alshareef,&nbsp;Colin Campbell,&nbsp;Steven M. Graves","doi":"10.1111/jnc.70554","DOIUrl":"10.1111/jnc.70554","url":null,"abstract":"<p>Methamphetamine (meth) is an addictive psychostimulant that induces monoamine oxidase (MAO)-dependent mitochondrial oxidative stress and MAO-dependent degeneration of substantia nigra pars compacta (SNc) dopamine neurons in male mice, suggesting that meth-induced mitochondrial oxidative stress is necessary for degeneration. However, the impact of chronic in vivo meth administration on SNc mitochondria is unclear. We therefore examined the impact of chronic meth administration on the expression of mitochondrial fission 1 (FIS1) and Dynamin-related protein 1 (DRP1), proteins involved in mitophagy, as well as mitochondrial density and mitochondrial function in the SNc. Male C57BL/6J mice received saline or meth (5 mg/kg; i.p.) for 28 days; chronic meth administration decreased SNc expression of both DRP1 and FIS1 proteins, suggesting impaired mitophagy. Consistent with this, mitochondrial density in SNc dopamine neurons was also increased. Moreover, this increase in mitochondrial density was MAO-dependent, suggesting that chronic meth-induced SNc degeneration is associated with an increase in mitochondrial density. To determine whether mitochondria were functional, high-resolution respirometry assessments were conducted using SNc tissue from mice treated with either chronic meth or saline. Results indicate that chronic in vivo meth administration decreased mitochondrial complex I as well as complex I + II oxidative phosphorylation capacities and coupling efficiencies in the SNc. Presented data suggest that chronic in vivo meth administration results in an accumulation of functionally compromised mitochondria in the SNc, which is associated with and may potentially contribute to chronic meth-induced neurodegeneration.</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 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70554","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149039272","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":"Neuroprotective Action of Agonists and Modulators of A1 Adenosine Receptors Upon Hyperexcitation: Mechanism of the Antiepileptic Activity and Role of Neuron-Glial Interaction","authors":"Polina E. Ryazantseva,&nbsp;Sergei G. Gaidin,&nbsp;Sergei A. Maiorov,&nbsp;Denis P. Laryushkin,&nbsp;Kristina A. Kritskaya,&nbsp;Alexey V. Berezhnov,&nbsp;Valentina N. Mal'tseva,&nbsp;Irina A. Gorbunova,&nbsp;Daria A. Shipilovskikh,&nbsp;Yulia O. Sharavyeva,&nbsp;Sergei A. Shipilovskikh,&nbsp;Ivan A. Andreev,&nbsp;Nina K. Ratmanova,&nbsp;Olga A. Ivanova,&nbsp;Igor V. Trushkov,&nbsp;Danila Y. Apushkin,&nbsp;Alexander I. Andreev,&nbsp;Eugenia A. Ahremenko,&nbsp;Margarita A. Maskaeva,&nbsp;Svetlana A. Batalshchikova,&nbsp;Artem M. Kosenkov","doi":"10.1111/jnc.70556","DOIUrl":"10.1111/jnc.70556","url":null,"abstract":"<div>\u0000 \u0000 <p>Hyperexcitation of neuronal networks is a key mechanism underlying excitotoxic neuronal death in conditions such as epilepsy, ischemic stroke, and traumatic brain injury. Given the inhibitory role of G_i-coupled receptors, A₁ adenosine receptors (A₁Rs) represent promising targets for neuroprotective and anticonvulsant therapy. In this study, we investigated the effects of A₁R agonists (CCPA and N⁶-CHA) and positive allosteric modulators (PAMs; PD81723 and VCP171) using in vitro models of hyperexcitation (glutamate excitotoxicity, NH₄Cl-induced hyperexcitation and bicuculline-induced epileptiform activity) and an in vivo picrotoxin-induced seizure model in mice. Calcium imaging, electrophysiology, and pharmacological inhibition were used to assess underlying mechanisms. A₁R agonists suppressed hyperexcitation in all in vitro models and reduced seizure severity and mortality in vivo. In hippocampal neuron–glial cultures, these effects were mediated by activation of both neuronal and astrocytic A₁Rs. In astrocytes, A₁R activation induced Ca²⁺ transients and promoted GABA release, with pharmacological evidence supporting the involvement of Gβγ subunits, phospholipase C, and Ca²⁺-dependent protein kinase C. PAMs also suppressed hyperexcitation in vitro; however, only chronic administration of VCP171 produced significant anticonvulsant effects in vivo, while acute treatment was ineffective. In conclusion, A₁R-mediated suppression of hyperexcitation involves both neuronal and astrocytic mechanisms, including astrocyte-dependent GABA release. A₁ adenosine receptors represent a promising therapeutic target, and their PAMs may provide therapeutic potential.</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 9","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017049","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}