Journal of Neurochemistry最新文献

{"title":"Calcium Signaling Related Genes in Migraine","authors":"Mohammad Taheri,&nbsp;Ashkan Pourtavakoli,&nbsp;Solat Eslami,&nbsp;Arezou Sayad,&nbsp;Soudeh Ghafouri-Fard","doi":"10.1111/jnc.70112","DOIUrl":"https://doi.org/10.1111/jnc.70112","url":null,"abstract":"<div>\u0000 \u0000 <p>Calcium is essential for the growth of neurons during infancy as well as transmission of signals between neurons; thus, the related signaling pathways might contribute to the pathogenesis of brain disorders. Voltage-gated calcium channels are widely expressed in the trigeminovascular system and are regarded as important contributors to some forms of familial migraines. In fact, these channels participate in the migraine initiation events. We compared the expression of genes coding for ion channels, including <i>SLC1A1</i>, <i>SLC25A12</i>, <i>ATP2B2</i>, and their associated lncRNAs, namely <i>LINC01231</i>, <i>lnc-SLC25A12</i>, and <i>lnc-MTR-1</i>, between migraineurs and healthy controls. All mentioned genes and lncRNAs, except for <i>ATP2B2</i> and <i>LINC01231</i>, were shown to be up-regulated in total migraineurs compared with controls. Moreover, the expression levels of ATP2B2 were higher in patients with aura compared with those without aura (Expression ratio (95% CI) = 5.83 (2.93–11.59), <i>p</i> &lt; 0.0001). Yet, SLC25A12 was down-regulated in patients with aura as compared with those without aura (Expression ratio (95% CI) = 0.21 (0.11–0.42), <i>p</i> = 0.004). Notably, we demonstrated high specificity and sensitivity values for some genes in the differentiation of migraineurs from healthy controls. Taken together, we demonstrated significant over-expression of a number of ion channel and transporter genes and their related lncRNAs in migraineurs and suggested these genes as potential markers for this neurological condition.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264650","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":"Preface to the Special Issue “Autism Spectrum Disorder: From Genes to Therapies”","authors":"Carlo Sala","doi":"10.1111/jnc.70123","DOIUrl":"https://doi.org/10.1111/jnc.70123","url":null,"abstract":"<p>Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by repetitive behaviors and deficits in social interaction and communication. While its exact etiology remains unclear, both genetic and environmental factors contribute to its development. The following preface provides a synthesis of six review articles and five original research studies published in this issue that explore various mechanisms potentially underlying ASD pathology. These publications collectively investigate a range of potential mechanisms underlying ASD pathology, including altered neural connectivity, synaptic dysfunction, immune dysregulation, and epigenetic modifications.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70123","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244571","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 Sensory Information Processing: The Essential Role of Astrocytes","authors":"Juliana M. Rosa,&nbsp;Juan Aguilar","doi":"10.1111/jnc.70113","DOIUrl":"https://doi.org/10.1111/jnc.70113","url":null,"abstract":"<p>One of the most fundamental abilities of the nervous system is to perceive, integrate, and process sensory inputs from the external environment. This physiological ability, known as sensory information processing, has been extensively studied using diverse experimental models, ranging from in vivo vertebrates and invertebrates to in vitro and computational approaches. Most of these seminal studies have primarily focused on neuronal components, providing critical insights into the principles of excitation and inhibition circuit dynamics and anatomical wiring. However, studies in the last decade have shed light on the important role of astrocytes in sensory information processing. The astrocytic effect on controlling the strength and gain of sensory neuronal responses is particularly evident in awake and freely moving animals, where their modulation has a direct influence on behavioral output, positioning them as cell targets to understand sensory processing as a whole in brain (dys)function. In this review, we draw attention to new research that casts doubt on the conventional neurocentric theories of sensory processing and highlights the growing influence of astrocytes on how sensory processing is shaped across modalities.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70113","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244248","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":"Multi-Omic Analysis of Glutamate Excitotoxicity in Primary Neuronal Cultures","authors":"Jennifer H. Nguyen,&nbsp;Xiaolu Zhang,&nbsp;Hunter M. Eby,&nbsp;Khaled Alganem,&nbsp;William G. Ryan,&nbsp;Ali Sajid lmami,&nbsp;Anna E. Lundh,&nbsp;Anvitha R. Madhavaram,&nbsp;James D. Bretz,&nbsp;Ethel Tackie-Yarboi,&nbsp;Kelsee Zajac,&nbsp;William S. Messer Jr.,&nbsp;Isaac T. Schiefer,&nbsp;Robert E. McCullumsmith","doi":"10.1111/jnc.70110","DOIUrl":"https://doi.org/10.1111/jnc.70110","url":null,"abstract":"<p>Glutamate excitotoxicity plays a critical role in neurodegeneration by triggering NMDA receptor hyperactivation, leading to elevated synaptic calcium levels and subsequent neuronal death. To better understand how glutamate affects neurons in neurological diseases, we conducted a comprehensive analysis of molecular changes at the transcriptome and kinome levels. We used primary cortical cultures from rat embryos to study glutamate-induced excitotoxicity. Intermediate doses of glutamate (250 μM) produced significant neurotoxic effects, whereas high and low doses resulted in less cell mortality, aligning with previous findings related to calcium influx. Transcriptional analysis identified BTG2, NPAS4, and CCN1 as the most significantly differentially expressed genes following 250 μM glutamate treatment in neurons. Dkk2, a Wnt antagonist, exhibited the highest log fold change among the significantly differentially expressed genes. Gene set enrichment analysis identified 1127 significant pathways. Perturbagen analysis revealed 2811 unique concordant signatures and 1071 unique discordant signatures. Kinome array profiling indicated activation of PKA and PKG kinases, which regulate signaling pathways essential for synaptic plasticity-related gene expression. Multi-omic integration of transcriptome and kinome data revealed enrichment of response to oxidative stress, actin filament organization, and regulation of apoptotic processes pathways. The Wnt signaling pathway emerged as a pivotal factor in the early stages of axon differentiation and growth, as well as in shaping axonal behavior and dendrite development. Moreover, the interplay between MAPK and Wnt signaling pathways likely impacts cellular differentiation processes. Our findings highlight a prominent role for p38/MAPK and stress-activated MAPK pathways, with specific activation of the MAPK/ERK signaling pathway in response to excitotoxic neuronal damage in vitro. In conclusion, glutamate excitotoxicity induces molecular changes at the transcriptome and kinome levels that include elements of the MAPK and WNT biological pathways.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70110","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144220281","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":"CacyBP/SIP Protein Regulates the Length and Branching of Neuronal Processes During Cortical Development","authors":"Katarzyna Bartkowska,&nbsp;Krzysztof Turlejski,&nbsp;Anna Filipek,&nbsp;Ruzanna Djavadian","doi":"10.1111/jnc.70115","DOIUrl":"https://doi.org/10.1111/jnc.70115","url":null,"abstract":"<div>\u0000 \u0000 <p>In mammals, CacyBP/SIP (calcyclin-binding protein/Siah-1-interacting protein) is widely expressed in different types of cells, including brain cells. CacyBP/SIP is involved in various cellular processes, among them proliferation, suggesting its role in tumorigenesis. In this work, we aimed to examine the role of CacyBP/SIP in cortical brain cells during developmental neurogenesis of the cerebral cortex in the opossum, <i>Monodelphis domestica</i>. Our results revealed that CacyBP/SIP is expressed in neurons and oligodendrocytes but not in astrocytes within the mature six-layered opossum brain. In the developing cortex of opossums at postnatal day (P) 15, we observed higher levels of CacyBP/SIP in the cortical plate, where newly generated neurons settle, compared to the subventricular neurogenic zone, where stem/progenitor cells reside. Next, we carried out experiments on primary cell cultures derived from the cerebral cortex or the anterior commissure of the opossum at two different developmental stages. We found that inhibition of CacyBP/SIP expression did not have any impact on proliferation and differentiation of cortical neurons. However, knockdown of CacyBP/SIP resulted in excessive branching of the dendritic tree and axon arbors of cortical neurons cultured from opossums at P15, which is a developmental stage corresponding to the formation of upper cortical layers. At this stage, cortical neuron axons reach the anterior commissure, that is the main fiber tract connecting the two cerebral hemispheres in marsupials, where they become myelinated by oligodendrocytes. We examined cells cultured from the anterior commissure at P35–38 during gliogenesis and observed that CacyBP/SIP did not affect the process of oligodendrogenesis or astrogenesis. Based on our results, we suggest that CacyBP/SIP is critical for arresting the branching and lengthening of dendrites and axons during formation of the cerebral cortex.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>\u0000 </div>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144220292","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 Bird's-Eye View of Glycolytic Upregulation in Activated Brain: The Major Fate of Lactate Is Release From Activated Tissue, Not Shuttling to Nearby Neurons","authors":"Gerald A. Dienel,&nbsp;Douglas L. Rothman,&nbsp;Silvia Mangia","doi":"10.1111/jnc.70111","DOIUrl":"https://doi.org/10.1111/jnc.70111","url":null,"abstract":"<p>Glucose is the major, obligatory fuel for the brain, and nearly all glucose is oxidized in the awake, resting state. However, during activation, much of the glucose is not oxidized even though adequate oxygen is available, ATP demand is increased, and glycolysis generates less ATP than oxidation. The fate of the lactate produced by glycolysis is a highly debated topic, in part because its origin and fate in the living brain are difficult to measure. One idea has been that astrocytes generate lactate and shuttle it to neurons as a major fuel, but critical elements of the shuttle model are not validated, and there is no compelling evidence to support shuttling coupled with oxidation in vivo. Metabolic brain imaging reveals rapid loss of labeled metabolites of glucose from activated tissue that is mediated by lactate transporters and gap junctional trafficking among astrocytes. Lactate is highly labeled by [¹³C- and ¹⁴C]glucose, it is diffusible, and it is quickly released to blood and the perivascular-lymphatic drainage system. During intense sensory stimulation, astrocytic glycogen is consumed at half the rate of glucose by all brain cells; it is a major fuel. The oxygen-carbohydrate metabolic mismatch increases when glycogen is included in the calculation, revealing that glycogen is not oxidized. Although the energetics of brain activation is complex, metabolic modeling with comparison to a wide range of experimental data relating metabolism to neurotransmission strongly supports two concepts: (i) glycogenolysis in astrocytes spares blood-borne glucose for activated neurons, and (ii) the increase in cerebral blood flow in excess of oxygen consumption removes protons produced by glycolytic metabolism to maintain tissue pH, pO₂, and pCO₂ homeostasis. Several studies have identified processes and situations that involve neuronal aerobic glycolysis, and a better understanding of the roles of glycolysis in neuron-astrocyte interactions and functional metabolism in the normal and diseased brain is required.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144220293","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":"Acute Effects of Four Major Trace Amines on Zebrafish Behavioral, Neurochemical, and Neuroendocrine Responses","authors":"Thalia M. Quintanilha,&nbsp;Pietra M. Costa,&nbsp;Ana L. S. Cardoso,&nbsp;Gabrieli S. Battú,&nbsp;Leonardo M. Bastos,&nbsp;Bruno P. dos Santos,&nbsp;Talise E. Müller,&nbsp;Tiago F. de Oliveira,&nbsp;Angelo Piato,&nbsp;Allan V. Kalueff,&nbsp;Murilo S. de Abreu","doi":"10.1111/jnc.70116","DOIUrl":"https://doi.org/10.1111/jnc.70116","url":null,"abstract":"<p>Trace amines are biologically active compounds endogenously synthesized in the brain in small amounts and structurally resembling biogenic amines. Acting via specific trace amine-associated receptors (TAARs), they induce robust behavioral and physiological effects in humans and animals. However, although TAAR ligands have recently been suggested as novel putative anxiolytics, their central effects and evolutionary conservation of activity remain poorly understood. Here, we evaluated the acute effects of four major trace amines (beta-phenylethylamine, tryptamine, tyramine, and octopamine) on zebrafish anxiety-like and social (shoaling) behavior, as well as neurochemical and neuroendocrine (cortisol) responses. Beta-phenylethylamine, at a low concentration (12 μg/L), caused overt anxiolytic-like effects and reduced brain acetylcholine levels; at a high concentration (1000 μg/L) increased zebrafish anxiety-like behavior and whole-body cortisol levels. Acute tryptamine exposure (7 mg/L) evoked an anxiogenic-like effect, reduced shoaling and social interaction, and elevated brain acetylcholine and whole-body cortisol. Acute exposure to tyramine (15 μg/L) and octopamine (125, 500, and 1500 μg/L) induced similar anxiogenic-like effects, accompanied by increased whole-body cortisol without altering brain acetylcholine levels. Collectively, these findings not only emphasize the important role of trace amines in brain and behavior but support the growing complexity of their CNS effects in vivo across taxa and highlight the relevance of zebrafish models for drug screening based on targeting brain TAARs.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70116","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144220295","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":"Exploring Iron Deposition Patterns Using Light and Electron Microscopy in the Mouse Brain Across Aging and Alzheimer's Disease Pathology Conditions","authors":"Victor Lau,&nbsp;Jared VanderZwaag,&nbsp;Colin J. Murray,&nbsp;Marie-Ève Tremblay","doi":"10.1111/jnc.70086","DOIUrl":"https://doi.org/10.1111/jnc.70086","url":null,"abstract":"<p>Alzheimer's disease (AD) involves cognitive decline, possibly via multiple concurrent pathologies associated with iron accumulation. To investigate if iron accumulation in AD is more likely due to pathological iron-rich compartments, or a compensatory response of iron within oligodendrocytes to disease progression, we sought to quantify iron-rich staining (via Perl's diaminobenzidine; DAB). Healthy wild-type (WT) and APP^Swe-PS1Δe9 (APP-PS1; amyloid-beta overexpressing) male mice were examined during middle age, at 14 months. The frontal cortex, a brain region affected over the course of dementia progression, was investigated. Iron-rich compartments were found across genotypes, including oligodendrocytes and immune cells at the blood–brain barrier, and exclusively amyloid plaques in the APP-PS1 genotype. A semi-automated approach was employed to quantify the staining intensity of iron-rich compartments with light microscopy. Mouse frontal cortex of each genotype was also assessed qualitatively and ultrastructurally with scanning electron microscopy, to novelly discern and confirm iron-rich staining (via Perl's DAB). We found parenchymal iron staining corresponding to oligodendrocytes, pericytes, astrocytes, microglia and/or infiltrating macrophages, and amyloid plaques; increased iron deposition and clustering were detected in middle-aged male APP-PS1 versus WT frontal cortex, supporting that AD pathology may involve greater brain iron levels and local clustering. Unexpectedly, iron-rich cells were enriched at the central nervous system (CNS) interface and perivascular space in control and APP-PS1 mouse models, with ultrastructural examination revealing examples of these cells loaded with many secretory granules containing iron. Together, our results provide novel exploration and confirmation of iron-rich cells/compartments in scanning electron microscopy and reinforce literature that iron deposition is relatively increased in AD over healthy cognitive aging and involves greater local clusters of iron burden. Increased iron burden along the aging trajectory, regardless of cognitive status, may also be attributed to novelly discovered iron-rich cells secreting granules along the CNS border.\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":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70086","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214192","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":"Hippocampal-Specific Insulin Resistance Elicits Synaptic Effects on Glutamate Neurotransmission","authors":"Jennifer M. Erichsen,&nbsp;Jennifer L. Woodruff,&nbsp;Claudia A. Grillo,&nbsp;Gerardo G. Piroli,&nbsp;Jim R. Fadel,&nbsp;Lawrence P. Reagan","doi":"10.1111/jnc.70083","DOIUrl":"https://doi.org/10.1111/jnc.70083","url":null,"abstract":"<p>Impaired insulin signaling in brain regions such as the hippocampus is thought to contribute to the cognitive deficits associated with conditions such as mild cognitive impairment and Alzheimer's disease. We have previously demonstrated a number of adverse effects in rats with hippocampal-specific insulin resistance, including hippocampal structural defects, impairments in hippocampal-dependent learning and memory, neuroplasticity deficits, behavioral despair, and anxiety-like behaviors. Additionally, we showed that hippocampal-specific insulin resistance decreased the serine phosphorylation of GluA1 and expression of GluN2B. These effects on postsynaptic glutamate receptors were particularly fascinating, due to the proposed theory of the glutamatergic system as a facilitator of hippocampal synaptic transmission. However, the synaptic effects of hippocampal-specific insulin resistance with regard to glutamate neurotransmission had yet to be elucidated. To address this question, we examined hippocampal glutamate neurochemistry and expression of glutamatergic synaptic proteins in rats with hippocampal-specific insulin resistance. We also examined the ability of intranasal insulin to impact glutamatergic synapses. We found decreased synaptic concentrations of glutamate in the hippocampus, likely a result of reduced hippocampal vGluT2 expression. Additionally, hippocampal glutamate efflux was significantly increased in rats with hippocampal-specific insulin resistance in response to a high (12 U), but not a low (0.072 U), dose of intranasal insulin. Our findings indicate that hippocampal-specific insulin resistance elicits synaptic plasticity deficits in glutamatergic synapses, which may be overcome by intranasal insulin administration.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70083","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144190942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered Vesicular Acetylcholine Transporter Expression Regulates Acetylcholine Abundance in the Brain of Drosophila melanogaster","authors":"Rohina A. Nemat,&nbsp;Timothy Chaya,&nbsp;Angeline-Claudia Atheby,&nbsp;Hakeem O. Lawal","doi":"10.1111/jnc.70109","DOIUrl":"https://doi.org/10.1111/jnc.70109","url":null,"abstract":"<p>The neurotransmitter acetylcholine (ACh) plays a central role in the regulation of vital neurological processes like cognition. As a result, increases or decreases in neuronal cholinergic signaling lead to an impairment in learning and memory. Although much about how acetylcholine is regulated is known, the mechanism through which alterations in cholinergic signaling affect changes in ACh-linked behavior is not fully understood. Importantly, the nature of the relationship between vesicular acetylcholine packaging and its release at the synaptic cleft is also unclear. We are interested in using the vesicular acetylcholine transporter (VAChT), which mediates the packaging and transport of acetylcholine (ACh) for exocytotic release, to elucidate the ways in which ACh loading alters its release and metabolism. We used both an overexpression of VAChT and two <i>Vacht</i> mutant lines, <i>Vacht</i>^<i>2</i> and <i>Vacht</i>^<i>8</i>, to increase or decrease the gene's expression respectively. Taking a combined immunohistochemical and biochemical approach, we measured the expression of ACh in VAChT overexpressors, and followed up those studies with an assay for ACh levels as a means of quantifying ACh storage and those of choline, its degradation product. We report that consistent with its well-known role in mediating ACh release, the VAChT overexpression line has elevated total head ACh levels in females but not males while <i>Vacht</i> mutants show strong reductions. By contrast, choline levels are elevated in VAChT overexpressors but unchanged in <i>Vacht</i> mutants. These findings are supported by immunolocalization studies in the fly brain in which the VAChT overexpressors show both elevated ACh in and around ACh neurons and an increased localization to synaptic release sites. When we analyzed the immunostaining studies by sex, we found that in contrast to the neurochemical studies, both males and females had elevated ACh levels, while the two <i>Vacht</i> mutants had reductions in that neurotransmitter's levels. By our estimation, these data represent the first time that acetylcholine has been measured directly in VAChT overexpression and <i>Vacht</i> mutants in <i>Drosophila</i> and demonstrate a consistency with findings from mammalian studies.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"169 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144190939","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}