Journal Of Neurochemistry[JOURNAL]
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200 papers
A PARK9 iPSC-Derived Dopaminergic Neuron Model Enables Drug Screening Targeting Autophagy-Lysosome Pathway Dysfunction in Parkinson's Disease.
Tsukiboshi KI, Ishikawa KI, Yamaguchi A … +6 more , Arai K, Kanai K, Tsunemi T, Okano H, Hattori N, Akamatsu W
J Neurochem · 2026 Jul · PMID 42400323 · Publisher ↗
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 inc...
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 ATP13A2 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.
Opposing Estrous Cycle-Dependent Norepinephrine and Dopamine Regulation in Response to Methamphetamine.
Bhimani RV, Pauly RC, Mietlicki-Baase EG … +1 more , Park J
J Neurochem · 2026 Jul · PMID 42400314 · Publisher ↗
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...
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.
Exercise Snacking in Alzheimer's Disease: A Mechanistic Rationale Based on Repeated Exerkine Signaling.
Sousa RAL, Costa JMM, Pereira RRS … +3 more , Vieira LCDR, Magalhães CODE, Dias-Peixoto MF
J Neurochem · 2026 Jul · PMID 42400308 · Full text
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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.
Geoghegan EM, Hagenauer MH, Hernandez E … +9 more , Espinoza S, Flandreau EI, Nguyen PT, Santiago AN, Bhuiyan MR, Mensch S, Watson SJ, Akil H, Hen R
J Neurochem · 2026 Jul · PMID 42396602 · Full text
Depression can be treated with traditional pharmaceuticals targeting monoaminergic function, nontraditional drug classes and neuromodulatory interventions. To identify mechanisms of action shared across clinically-effect...
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 (hippocampus: June 24, 2024, cortex: 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 n = 313 samples), with approximately half representing traditional versus nontraditional antidepressants. Of 16 439 analyzed genes, 58 were consistently differentially expressed (False Discovery Rate (FDR) < 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 n = 233 samples). Of 15 583 analyzed genes, only one was consistently differentially expressed (FDR < 0.05: Atp6v1b2), 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.
Splice Type-Specific Effects of Gαo Subunits on Cerebellar Anatomy and Synapse Formation.
Höltje M, Wolkowicz A, Ahnert-Hilger G
J Neurochem · 2026 Jul · PMID 42388035 · Full text
This study investigated the effect of single Gα and Gα, as well as double Gα knockout on the cerebellar anatomy and synapse formation. The alpha subunit of the G protein Go exists in two splice variants. Knockout of cert...
This study investigated the effect of single Gα and Gα, as well as double Gα knockout on the cerebellar anatomy and synapse formation. The alpha subunit of the G protein Go exists in two splice variants. Knockout of certain Gαo subtypes result in strong-mainly motor-deficits in mice, and mutations in the responsible gene locus in humans can result in severe encephalopathies. We aimed to decipher the hitherto incompletely understood contribution of the individual Gα subunits to the anatomy and synapse formation of the cerebellum. Knockout of Gα reduced the size of the cerebellum by 11%, accompanied by maximal reductions of the molecular layer thickness in the central lobule III (-30%) and molecular layer area in the uvula (-33%). Knockout of Gα increased cerebellar size, molecular layer thickness in central lobule II (+18.6%), and area of the culmen (+37%). Combined deletion of Gα and Gα reduced cerebellar size by 12%, molecular layer thickness and area of the declive (by -27.3% and -23.4%, respectively). Moreover, VGLUT2-positive climbing fiber contacts to Purkinje cells were reduced in Gα knockout mice (on average by 40%). Similarly, VGLUT1 expression was reduced (on average by 17.3%). The knockout of Gα promoted climbing fiber contacts (+14.3% on average, at a maximum of +52.6% in the central lobule II), VGLUT1 was less affected. Double knockout mice exhibited negative effects on VGLUT2 (-35% overall number) and VGLUT1 (-23% on average in expression levels). VGAT-positive synaptic contacts were also diminished for Gα and double knockout (-25% and -31% overall number, respectively) and increased for Gα knockout (+13% on average). In line with this, negative effects on the dendritic outgrowth of Purkinje cells were observed in both Gα and Gα mice, while knockout of Gα promoted dendrite outgrowth. Taken together, the two Gαo splice variants contrarily contribute to the development of the cerebellum, with Gα representing the dominant subunit.
Neurobiological and Behavioral Consequences of Prenatal Methadone or Buprenorphine Exposure: Insight From Animal Models.
Nyberg H, Andersen JM
J Neurochem · 2026 Jul · PMID 42381503 · Publisher ↗
The marked increase in opioid use over the past three decades has been accompanied by increased use of medications for opioid use disorder (MOUD), including during pregnancy. However, methadone and buprenorphine, the pri...
The marked increase in opioid use over the past three decades has been accompanied by increased use of medications for opioid use disorder (MOUD), including during pregnancy. However, methadone and buprenorphine, the primary MOUDs, cross the placenta and the immature fetal blood-brain barrier, raising concerns about potential effects on offspring development. In this review, we summarize experimental animal studies published over the past 25 years examining neurobiological and behavioral outcomes following prenatal exposure to methadone or buprenorphine. Although animal models cannot fully establish human outcomes, they offer important insights into causal relationships and underlying biological mechanisms that are difficult to study in clinical populations. Our aims were to compare the effects of methadone and buprenorphine, assess sex-specific and intergenerational effects, and identify areas where further preclinical research is needed. In total, 53 studies were identified. Collectively, the findings show that prenatal MOUD exposure is associated with alterations in several key neurobiological processes, including opioid receptor expression and signaling, neurotransmitter systems, neurotrophic pathways, neurogenesis and neuronal maturation, synaptic organization and plasticity, myelination, structural development, and neuroinflammation. Behavioral outcomes include alterations in cognitive function, affective and social behaviors, reward-related behavior, and pain sensitivity. Evidence for sex-specific and intergenerational effects is increasing, but the overall evidence base remains limited. Substantial variability in findings limits the ability to draw definitive conclusions. Future studies should integrate mechanistic and functional approaches and focus on comparisons between methadone and buprenorphine, sex-specific differences, and intergenerational effects using translationally relevant models. More knowledge is crucial for supporting evidence-based decision-making during pregnancy and for minimizing potential long-term risks to offspring.
Parkinson's Disease Cell Transplantation Therapy: A New Dawn With Pluripotent Stem Cell-Based Therapy.
Nakanishi E, Yamakado H, Sawamoto N … +2 more , Takahashi J, Takahashi R
J Neurochem · 2026 Jul · PMID 42381498 · Full text
Parkinson's disease (PD), a prevalent neurodegenerative disorder, is characterized by progressive loss of dopaminergic neurons in the midbrain. While dopamine replacement therapy effectively manages early symptoms, its l...
Parkinson's disease (PD), a prevalent neurodegenerative disorder, is characterized by progressive loss of dopaminergic neurons in the midbrain. While dopamine replacement therapy effectively manages early symptoms, its long-term use leads to motor complications, highlighting the urgent need for treatments that directly address the underlying pathological changes. Cell transplantation, which aims to replace the lost dopaminergic neurons, has emerged as a promising approach. Early attempts using fetal ventral mesencephalic (fVM) tissue showed proof-of-concept, with some patients experiencing long-term motor improvement. However, these trials have been hampered by inconsistent results, graft-induced dyskinesia (GID), and significant ethical and logistical issues related to tissue supply. These challenges have shifted the focus to pluripotent stem cells (PSCs), including human-induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), which offer a stable, ethically sound, and scalable source of high-quality cells. Recent clinical trials using PSCs suggest a turning point. All reported clinical trials demonstrated the safety and feasibility of this approach. The need for long-term safety and efficacy data, patient stratification, and techniques to improve graft survival are key areas of future research. Nevertheless, recent clinical trial successes suggest that cell transplantation is moving beyond symptomatic relief to become a truly restorative therapy for PD.
Neural Organoid Models as a Platform for Studying Disease Mechanisms in Amyotrophic Lateral Sclerosis.
Eigenhuis KN, Ferrer RM, Pasterkamp RJ
J Neurochem · 2026 Jul · PMID 42381488 · Full text
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons leading to muscle wasting. However, structural and molecular abnormalities, including cortical thinning an...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons leading to muscle wasting. However, structural and molecular abnormalities, including cortical thinning and TDP-43 pathology, extend into frontal, parietal, and temporal areas, pointing to defects across broader cortical regions. The advent of human induced pluripotent stem cell (hiPSC) technology has enabled the generation of human-specific brain cell types in vitro. Here, we provide an overview of the three-dimensional (3D) hiPSC-derived neural organoid platforms used to model cortical structures and to study cortical ALS-associated phenotypes. We review which pathological hallmarks have been recapitulated in these organoids and discuss disease phenotypes reported to date. Further, we comprehensively cover different neural organoid models and experimental strategies, including patient-derived hiPSC models and exogenous pathology induction, while addressing current technical challenges. Together, these advances position neural organoids as an emerging tool to study cell-type-specific and circuit-level mechanisms related to cortical changes in ALS.
LRRK2 Mutation Alters Dopamine D2 Receptor Localization in Induced Pluripotent Stem Cells-Derived Astrocytes From Parkinson's Disease Patients: Implications for Neuronal Damage.
Mutti V, Bono F, Tomasoni Z … +11 more , Fadel D, Gnutti C, Sbrini G, Gaudenzi C, Salvi V, Bosisio D, Russo I, Bolognin S, Schwamborn JC, Missale C, Fiorentini C
J Neurochem · 2026 Jul · PMID 42381446 · Full text
Astrocytes, the most abundant glia subtype, exert a wide range of functions, many of which are essential for maintaining neuronal homeostasis. A variety of neurotransmitter receptors are expressed on astrocytes allowing...
Astrocytes, the most abundant glia subtype, exert a wide range of functions, many of which are essential for maintaining neuronal homeostasis. A variety of neurotransmitter receptors are expressed on astrocytes allowing them to sense extracellular signals and respond by releasing neuroactive mediators. Among them, a wide variety of G protein-coupled receptors have been detected, including those for dopamine (DA), known to play a major role in modulating astrocytic activity. Evidence that astrocytic DA D2 receptors (D2R) increase the release of trophic factors and suppress neuroinflammation has been provided. Thus, DA signaling in astrocytes may be crucially involved in the mechanisms underlying the degeneration of DA neurons in Parkinson's disease (PD). In this study, human astrocytes were generated from induced pluripotent stem cell (iPSC) lines derived from two PD patients bearing G2019S LRRK2 kinase activating mutation. The effect of the PD-related mutation in astrocytes was analyzed, focusing on DA receptor's expression and localization. As expected, astrocytes carrying G2019S mutation in LRRK2 displayed a reactive phenotype with increased secretion of inflammatory cytokines and reduced ability to support DA neurons' trophism in astrocytes/neurons co-culture experiments. Intriguingly, PD astrocytes exhibited reduced membrane expression of D2R. Inhibiting the abnormally increased kinase activity was able to revert the PD astrocytes' reactive phenotype and to rescue the D2R membrane localization. We thus provide new insights into how G2019S mutation in LRRK2, by disrupting the astrocytic physiological localization of D2R, may impair protective DA signaling, resulting in increased neuroinflammation and neuronal damage.
GM-Oligosaccharide Rescues Rotenone-Impaired Neuronal Polarization Through RhoA/ROCK Modulation and Mitochondrial Protection.
Rodríguez PEA, Colmano GN, Pellegrini A … +7 more , Mariani ME, Rosso SB, Quassollo G, Helguera P, Bisbal M, Fidelio GD, Sanchez MS
J Neurochem · 2026 Jul · PMID 42381431 · Publisher ↗
Neuronal polarization is a fundamental process in the formation of functional neural circuits, relying on the precise coordination between cytoskeletal regulatory signals and mechanisms that sustain cellular integrity. D...
Neuronal polarization is a fundamental process in the formation of functional neural circuits, relying on the precise coordination between cytoskeletal regulatory signals and mechanisms that sustain cellular integrity. Disruption of these processes compromises neuronal differentiation and survival, and various neurotoxic compounds, including certain pesticides, have been associated with such dysfunctions. In this context, identifying molecules that counteract these detrimental effects is of significant therapeutic interest. Neuronal polarization is essential for the establishment of functional neural circuits and relies on coordinated regulation of actin cytoskeleton dynamics, RhoA/ROCK signaling, and mitochondrial function. Here, we investigated the neuroprotective and neurorestorative potential of the ganglioside GM1 and its oligosaccharide derivative, osGM1, in primary hippocampal pyramidal neurons derived from embryonic day 18 (E18) rat embryos exposed to the mitochondrial neurotoxin rotenone. Rotenone induced a marked arrest of neuronal development, impaired axonal elongation, and disrupted mitochondrial organization and functional status. Both GM1 and osGM1 promoted recovery of neuronal polarity and axonal growth, exerting protective and restorative effects even under continuous toxin exposure, with osGM1 showing superior efficacy. Notably, osGM1 also reversed axonal growth deficits caused by pathological actin stabilization. Mechanistically, osGM1 normalized rotenone-induced hyperactivation of the RhoA/ROCK pathway without altering basal signaling and partially restored mitochondrial network integrity and functional activity. Collectively, these findings identify osGM1 as a multi-target modulator of cytoskeletal and mitochondrial dysfunction and support its translational potential as a therapeutic strategy to counteract neurotoxin-induced neuronal damage.
Norepinephrine Couples Astrocytic Metabolism to mTOR-Driven Protein Synthesis.
Cabrera-Cabrera F, Tull H, Urone G … +4 more , Utt A, Kuhtinskaja M, Zorec R, Koppel I
J Neurochem · 2026 Jul · PMID 42381423 · Publisher ↗
Norepinephrine is a neuromodulator that regulates diverse physiological processes in the central nervous system, including astrocytic metabolism. While its metabolic actions in astrocytes are well characterised, its role...
Norepinephrine is a neuromodulator that regulates diverse physiological processes in the central nervous system, including astrocytic metabolism. While its metabolic actions in astrocytes are well characterised, its role in regulating protein synthesis remains unknown. Here, we show that norepinephrine robustly stimulates protein synthesis in rat primary cortical astrocytes in a time-dependent manner, comparable to that of insulin and serum. This effect is mediated predominantly by β-adrenergic receptors and is accompanied by activation of the mTOR-S6K signalling pathway. We further demonstrate that this translational response requires glycolytic activity and is preceded by a rapid depletion of astrocytic glycogen stores and a transient reduction in ATP levels. Together with growth factors, these findings identify protein synthesis as a previously unrecognised physiological target of norepinephrine in astrocytes and reveal a mechanism linking neuromodulatory signalling, metabolic state and mTOR-dependent translational control in the brain.
Preface to the Special Issue "Astrocytes in Cognition and Behavior".
Oliveira JF, Araque A
J Neurochem · 2026 Jun · PMID 42377314 · Publisher ↗
Astrocytes, once viewed as passive support cells in the central nervous system, are now recognized as active and dynamic regulators of neural function. Across multiple domains of central nervous system function, astrocyt...
Astrocytes, once viewed as passive support cells in the central nervous system, are now recognized as active and dynamic regulators of neural function. Across multiple domains of central nervous system function, astrocytes interact closely with neurons to influence synaptic transmission, plasticity, and behavior. These include key brain and spinal cord functions related to information processing that impact cognition and animal behavior. This Special Issue features 12 comprehensive reviews and original data articles that highlight key advances and ongoing challenges in this field. These works collectively reflect a major shift from a neuron-centered perspective to an integrated neuron-glia framework, in which astrocytes sense neuronal and neuromodulator activity and actively shape neural circuit function in health and disease contexts.
Astrocytic Regulation of Aberrant Perineuronal Net Formation in Mecp2-Null Neocortex.
Sinha A, Kowalchuk AM, Khatibi N … +2 more , Matthews RT, MacDonald JL
J Neurochem · 2026 Jun · PMID 42375118 · Full text
Rett syndrome (RTT), caused by mutations in MECP2, is a complex neurological disorder characterized by myriad physiological disruptions, including early closure of the critical period of developmental plasticity and prec...
Rett syndrome (RTT), caused by mutations in MECP2, is a complex neurological disorder characterized by myriad physiological disruptions, including early closure of the critical period of developmental plasticity and precocious formation of perineuronal nets (PNNs). PNNs are lattice-like substructures of extracellular matrix (ECM) that enwrap specific subpopulations of neurons. PNNs are essential in the modulation of neuronal plasticity and brain maturation, and their enzymatic disruption can partially restore plasticity in adults and improve memory. Although precocious PNN formation is well-established in RTT, little is known of the cellular, molecular, or biochemical underpinnings of their precocious formation, or whether precocious PNN formation is due to cell-autonomous or non-cell-autonomous mechanisms. While PNNs form on subsets of neurons throughout the brain, astrocytes secrete many ECM components that form PNNs, and they play a central role in controlling closure of the critical period. We find that Mecp2-null mouse astrocyte conditioned media induces the expression of the key PNN component Hapln1 and causes enhanced PNN formation on wildtype mouse neurons in vitro, suggesting that Mecp2-null astrocytes play a key role in the precocious formation of PNNs in RTT. Further, we identify increased expression of HAPLN1 and other PNN/ECM components in the developing mouse Mecp2-null cortex, and demonstrate that PNNs are structurally and biochemically mature at an earlier developmental stage. These results provide essential insight into the mechanisms and structure of aberrant PNNs in Mecp2-null cortex and identify potential new avenues for targeted rescue or reversal of the precocious closing of the critical period in RTT.
Comparison of Proteomic Analysis of Cerebrospinal Fluid From Neurological Patients With and Without Amyotrophic Lateral Sclerosis.
Sabetta E, Rallmann K, Taba P … +6 more , Pfaff AL, Poudel BH, Ferrari D, Locatelli M, Kõks S, Bergquist J
J Neurochem · 2026 Jun · PMID 42360043 · Full text
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness in both bulbar and extremity muscles, leading to a diverse clinical phenotype with motor and non-motor symp...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterised by progressive muscle weakness in both bulbar and extremity muscles, leading to a diverse clinical phenotype with motor and non-motor symptoms. Approximately 85% of ALS cases are sporadic (sALS), while the remaining 10%-15% are familial (fALS). Biological biomarkers of sporadic ALS remain poorly understood, hindering precise patient screening, delaying diagnosis and negatively affecting prognosis. This study aims to identify potential proteomic biomarkers by comparing the cerebrospinal fluid (CSF) of sALS patients with that of patients suffering from other neurological diseases. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for proteomic profiling of CSF samples from 24 sALS patients and 26 patients with other neurological diseases. The complete protein expression profiles were compared using a two-tailed Student's t-test, with a p < 0.05 considered statistically significant with additional FDR correction at the 0.1 level. Proteomic analysis of CSF samples identified significant quantitative changes in 96 proteins with threshold p < 0.05 and 74 proteins with FDR < 0.1 between sALS and non-ALS patients, including alterations in proteins associated with neurodegenerative processes, such as amyloid precursor proteins and inflammatory markers. CSF proteomic analysis reveals altered inflammatory and neurodegenerative metabolic pathways, providing valuable insights into the proteomic landscape of sALS. Several dysregulated proteins were consistent with the disease mechanisms highlighted in previous studies. These findings represent a step forward in developing personalised approaches for diagnosing and managing the disease.
Kynurenine Pathway Metabolite Levels in Drug Naïve and Risperidone Treated Schizophrenia: Insights From Systemic and Post-Mortem Brain Tissue Analysis.
Nikhil J, Thirumoorthy C, Sharma P … +3 more , Kumar V, Varambally S, Gokulakrishnan K
J Neurochem · 2026 Jun · PMID 42338096 · Publisher ↗
Kynurenine pathway (KP), the principal route of tryptophan (TRY) metabolism, is implicated in schizophrenia (SCZ), but findings remain inconsistent, particularly regarding peripheral-central associations and links to imm...
Kynurenine pathway (KP), the principal route of tryptophan (TRY) metabolism, is implicated in schizophrenia (SCZ), but findings remain inconsistent, particularly regarding peripheral-central associations and links to immune dysregulation. We measured KP metabolites, cytokines, and metabolic risk factors in serum from drug-naïve (DN) and risperidone-treated (RT) SCZ patients versus healthy controls (HC) as well as in post-mortem brain tissue from an independent cohort by assessing KP metabolites, enzyme expression (mRNA, protein) and cytokine profiles. We recruited a total of 227 participants from the clinical services of a large neuropsychiatric hospital, which included DN SCZ (n = 66), RT SCZ (n = 87), and HC (n = 74). Additionally, brain KP metabolite levels and the mRNA and protein expression of key enzymes and cytokines were evaluated in the dorsolateral prefrontal cortex (DLPFC) samples from the post-mortem cohort of 10 SCZ patients and 17 controls. KP metabolites were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Both DN and RT groups exhibited significantly reduced TRY (p < 0.05), elevated kynurenine (KYN), kynurenic acid (KYNA), KYN/TRY ratio and serotonin (SER) in serum (p < 0.001), alongside higher TNF-α, and IFN-γ and lower IL-10 (p < 0.001 for both). These alterations were correlated with metabolic risk factors, symptom severity of SCZ, and immune markers, and these remained associated with disease status after adjusting for confounders. Post-mortem analyses confirmed increased brain KYN (p < 0.05) and KYNA (p < 0.001) in the DLPFC of SCZ, accompanied by upregulation of Tryptophan 2,3-dioxygenase (TDO2) (p < 0.001) and Kynurenine aminotransferase II (KAT II) (p < 0.05) expression and elevated pro-inflammatory cytokines. Our findings provide convergent evidence for KP dysregulation in SCZ, linking immune activation with enhanced change toward KYNA synthesis both systemically and centrally. The observed alterations across independent serum and post-mortem brain cohorts support the potential relevance of these molecular signatures to SCZ pathophysiology and their possible therapeutic implications.
Sex-Dependent Neurochemical Encoding of Acute Social Experience in Adult CD1 Mice.
Azkona G, Díez-Solinska A, Saez-Atxukarro O … +3 more , Ochoteco-Perales L, Beitia-Oyarzabal G, Vegas O
J Neurochem · 2026 Jun · PMID 42333056 · Full text
Acute social interaction rapidly engages physiological and neurochemical systems, yet the extent to which these responses differ between sexes remains incompletely understood. Here, we investigated behavioural, endocrine...
Acute social interaction rapidly engages physiological and neurochemical systems, yet the extent to which these responses differ between sexes remains incompletely understood. Here, we investigated behavioural, endocrine and region-specific neurochemical responses to a brief social challenge using the social interaction test in adult male and female CD1 mice. Behavioural performance was comparable between sexes, with similar levels of social interaction and locomotor activity. In contrast, endocrine measures revealed a robust stress response, as corticosterone markedly increased after social challenge. Estradiol and progesterone levels also increased following the social challenge, whereas testosterone exhibited the expected sexual dimorphism. Neurochemical profiling revealed widespread and region-dependent effects. The brainstem showed manipulation-driven increases in glutamatergic and catecholaminergic markers across sexes. In the striatum, social interaction preferentially enhanced glutamatergic metabolites in males, whereas females displayed stronger monoaminergic signatures. The hippocampus exhibited the most pronounced sex-dependent modulation, involving amino-acid precursors, catecholaminergic turnover indices, noradrenergic metabolites and kynurenine-pathway ratios. By contrast, neurochemical organisation in the prefrontal cortex was predominantly shaped by baseline sexual dimorphism rather than acute social exposure. Correlation analyses between plasma hormones and regional neurochemical markers revealed limited and inconsistent associations, suggesting a relative dissociation between endocrine and neurochemical responses to the social challenge. Together, these findings demonstrate that acute social interaction induces broad endocrine and neurochemical adaptations while revealing distinct, region-specific sex signatures in neurochemical regulation.
Brainstem Astrocytes Regulate Estrus-Dependent Oscillations in Food Intake.
Ozkaya KS, Yalcin C, Haar EE … +2 more , Bhagat R, Browning KN
J Neurochem · 2026 Jun · PMID 42313475 · Full text
Previous studies have shown that dorsal vagal complex (DVC) astrocytes play important roles in homeostatic regulation of food intake and caloric balance, specifically upregulation of NMDA receptor-mediated glutamatergic...
Previous studies have shown that dorsal vagal complex (DVC) astrocytes play important roles in homeostatic regulation of food intake and caloric balance, specifically upregulation of NMDA receptor-mediated glutamatergic signaling to brainstem dorsal motor nucleus of the vagus (DMV) motoneurons restores caloric balance following exposure to caloric dense diets. DMV neurons are critical to the regulation of gastric functions, including motility, tone, and emptying; hence food intake and energy homeostasis. Prior studies have also shown that caloric intake in female rats fluctuates across the estrus cycle, with food intake being lowest during periods of high estrogen levels. The aim of the current study was to investigate whether these estrus-cycle dependent oscillations in food intake also involve DVC astrocyte adaptation. Immunohistochemical measurement of astrocytes across the estrus cycle uncovered an increase in glial-fibrillary acidic protein immunoreactivity (GFAP-IR) as well as an increase in astrocyte morphological complexity associated with high estrogen levels. Chemogenetic inhibition of DVC astrocytes eliminated food intake oscillations, whereas chemogenetic activation resulted in a consistent decrease in food intake, regardless of estrus status. Electrophysiological recordings from DMV neurons revealed that the estrus-dependent decrease in food intake was associated with activation of DMV NMDA receptors, and pharmacological inhibition of either estrogen receptors or brainstem astrocytes prevented this mechanism. In contrast, application of estradiol uncovered astrocyte- and NMDA-receptor dependent signaling to DMV neurons in low estrogen states. The findings of the present study demonstrate that DVC astrocytes and/or NMDA signaling play a fundamental role in estrogen-dependent fluctuations in food intake and energy homeostasis.
Ischemia-Induced Post-Translational Modifications of GLT-1 Mediate Aberrant Trafficking and Impaired Glutamate Uptake.
Gill SK, Reeb KL, Kroll M … +2 more , Mortensen OV, Fontana ACK
J Neurochem · 2026 Jun · PMID 42299780 · Full text
Glutamate transporters are essential for maintaining CNS homeostasis by clearing extracellular glutamate following synaptic transmission. Dysregulation of these transporters contributes to glutamate-mediated excitotoxici...
Glutamate transporters are essential for maintaining CNS homeostasis by clearing extracellular glutamate following synaptic transmission. Dysregulation of these transporters contributes to glutamate-mediated excitotoxicity across numerous neurological disorders, including ischemic stroke, underscoring their potential as therapeutic targets. However, the regulatory response of these transporters following ischemic insult remains poorly defined. In this study, using a model of oxygen-glucose deprivation in primary rat glial cultures, we report aberrant trafficking of the astrocytic glutamate transporter GLT-1 following ischemic insult. This response is characterized by increased transporter internalization and degradation, accompanied by reduced glutamate uptake capacity. Focusing on post-translational modifications (PTMs), we found that GLT-1 ubiquitination is markedly increased after ischemic insult and coincides with transporter internalization. Importantly, disrupting this ubiquitination interaction through mutation of C-terminal GLT-1 lysine residues restores GLT-1 surface expression and rescues glutamate uptake capacity through preventing early endosome 1 (EEA1)-mediated internalization. Additionally, we report that inhibition of C-terminal GLT-1 PTMs confers neuroprotection following ischemic insult in organotypic hippocampal brain slices. Together, these findings demonstrate that ischemia-induced dysregulation of GLT-1 trafficking plays a critical role in impaired glutamate clearance and cellular recovery, highlighting GLT-1 ubiquitination as a potential therapeutic target for ischemic injury.
Correction to "ATG14-Mediated SNARE Complex Activation Promotes ΔFosB Degradation to Ameliorate Levodopa-Induced Dyskinesia".
J Neurochem · 2026 Jun · PMID 42299747 · Publisher ↗
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The Long Haul: Microtubule Motors as the Essential Supply Line for Neuronal Longevity.
Turner ED, Twelvetrees AE
J Neurochem · 2026 Jun · PMID 42283497 · Full text
The extreme morphology and polarised architecture of neurons require the highly sophisticated microtubule transport system for both construction and lifelong survival. Genomic evidence from an expanding landscape of huma...
The extreme morphology and polarised architecture of neurons require the highly sophisticated microtubule transport system for both construction and lifelong survival. Genomic evidence from an expanding landscape of human mutations supports the essential role of the microtubule transport machinery. During neurodevelopment, mutations disrupt the proliferation and migration of neuronal precursors, as well as the initial establishment of polarity. In the mature nervous system, the reliance on microtubule transport shifts to the long-term maintenance of axon integrity and synaptic proteostasis. Across the motor proteins responsible for long distance transport in neurons, mutations highlight a specific vulnerability of long axons to transport failure in Hereditary Spastic Paraplegia (HSP), Charcot Marie Tooth disease Type 2 (CMT2), Spinal Muscular Atrophy (SMA), Perry Syndrome, and Amyotrophic Lateral Sclerosis (ALS) amongst others. Due to the role of microtubule motors in development and maintenance, there is frequently a phenotypic spectrum within a single gene of the microtubule transport system. For example, mutations in dynein motors are linked both to malformations of cortical development and specific motor neuron loss in SMA-LED (Spinal Muscular Atrophy with Lower Extremity Predominance). By synthesising genetic evidence, this review illustrates how specific molecular failures, ranging from motor-domain kinetics to cargo binding, can inform our understanding of neuronal homeostasis. Ultimately, we argue that microtubule transport is not merely a cellular utility, but a key determinant of neuronal longevity.
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