{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:35:56Z","timestamp":1787243756066,"version":"build-2736575974"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:00:00Z","timestamp":1750636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Pyridoxal 5\u2032-phosphate (PLP), the active form of pyridoxine (vitamin B6), is essential for converting glutamate into the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Severe consequences of PLP deficiency due to genetic defects are well known, but the impact of modest pyridoxine deficits remains unclear. Low pyridoxine levels have been associated with poor neurological outcomes in disease and injury, but it is uncertain whether this reflects a causal relationship or is a secondary consequence of inflammatory conditions. This study aimed to investigate the functional impact of moderate reductions in PLP activity on neuronal function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Primary mouse neuronal cultures were treated with amino-D-proline (ADP) to induce a moderate reduction in PLP activity to simulate a low pyridoxine environment. ADP concentrations were titrated to produce a small decrease in GABA expression without loss of GABAergic cells or innervation. Calcium signaling was assessed in live cells, and electrophysiological recordings were performed using multielectrode arrays to evaluate neural activity under baseline and mild pathological conditions (reduced magnesium, inflammatory environment).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>ADP-treated neurons exhibited increased calcium signaling frequency and intensity, consistent with a hyperactive phenotype. Under mild pathological conditions, calcium signaling and accumulation were further amplified. Electrophysiological recordings revealed increased neural activity, characterized by a higher frequency of short bursts of synchronous activity and random spikes. Chronic ADP treatment led to compensatory changes in neural activity, suggesting potential differences between acute and chronic pyridoxine deficiency.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study demonstrates that even a modest reduction in PLP activity induces transient neuronal hyperexcitability, which may enhance the pathological effects of disease, injury, and inflammation. These findings highlight the importance of pyridoxine in maintaining neural stability and suggest that low pyridoxine levels could contribute to neurological dysfunction. Further investigation is warranted to fully understand the clinical implications of mild pyridoxine deficiency.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2025.1621349","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:10:43Z","timestamp":1750637443000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Moderate pyridoxal phosphate deficiency enhances neuronal excitability and promotes calcium dysregulation"],"prefix":"10.3389","volume":"19","author":[{"given":"Valerie","family":"Girgis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashlyn","family":"Tharington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jadyn","family":"Trivett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Fitting","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick B.","family":"Meeker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clio","family":"Rubinos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.2174\/092986707780597899","article-title":"Pyridoxal 5\u2032-phosphate enzymes as targets for therapeutic agents","volume":"14","author":"Amadasi","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1542\/peds.94.3.318","article-title":"Glutamate in pyridoxine-dependent epilepsy: neurotoxic glutamate concentration in the cerebrospinal fluid and its normalization by pyridoxine","volume":"94","author":"Baumeister","year":"1994","journal-title":"Pediatrics"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1038\/351751a0","article-title":"Bell-shaped calcium-response curves of ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum","volume":"351","author":"Bezprozvanny","year":"1991","journal-title":"Nature"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/j.1469-7793.1997.00017.x","article-title":"Kinetics of Ca2+ release by InsP3 in pig single aortic endothelial cells: evidence for an inhibitory role of cytosolic Ca2+ in regulating hormonally evoked Ca2+ spikes","volume":"504","author":"Carter","year":"1997","journal-title":"J. Physiol."},{"key":"ref9001","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/S0002-9343(02)01528-0","article-title":"Abnormal vitamin B6 status is associated with severity of symptoms in patients with rheumatoid arthritis","volume":"114","author":"Chiang","year":"2003","journal-title":"Am. J. Med."},{"key":"ref9002","doi-asserted-by":"publisher","DOI":"10.1186\/ar1821","article-title":"Inflammation causes tissue-specific depletion of vitamin B6","volume":"7","author":"Chiang","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"17561","DOI":"10.1016\/S0021-9258(17)32478-X","article-title":"Rapid filtration studies of the effect of cytosolic Ca2+ on inositol 1,4,5-trisphosphate-induced 45Ca2+ release from cerebellar microsomes","volume":"269","author":"Combettes","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1152\/jn.2002.88.3.1461","article-title":"Involvement of calcium in rhythmic activity induced by disinhibition in cultured spinal cord networks","volume":"88","author":"Darbon","year":"2002","journal-title":"J. Neurophysiol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/j.yebeh.2015.08.015","article-title":"Pyridoxine deficiency in adult patients with status epilepticus","volume":"52","author":"Dave","year":"2015","journal-title":"Epilepsy Behav."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1152\/jn.00079.2015","article-title":"Quantification of bursting and synchrony in cultured hippocampal neurons","volume":"114","author":"Eisenman","year":"2015","journal-title":"J. Neurophysiol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1111\/j.1749-6632.1991.tb36509.x","article-title":"Subsecond kinetics of inositol 1,4,5-trisphosphate-induced calcium release reveal rapid potentiation and subsequent inactivation by calcium","volume":"635","author":"Finch","year":"1991","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1007\/BF00964920","article-title":"Effect of vitamin B-6 nutrition on the levels of dopamine, dopamine metabolites, dopa decarboxylase activity, tyrosine, and GABA in the developing rat corpus striatum","volume":"14","author":"Guilarte","year":"1989","journal-title":"Neurochem. Res."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/ni.3102","article-title":"Innate immunity in Alzheimer\u2019s disease","volume":"16","author":"Heneka","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/nrn3880","article-title":"Immune attack: the role of inflammation in Alzheimer disease","volume":"16","author":"Heppner","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1085\/jgp.95.6.1103","article-title":"Biphasic Ca2+ dependence of inositol 1,4,5-trisphosphate-induced ca release in smooth muscle cells of the guinea pig taenia caeci","volume":"95","author":"Iino","year":"1990","journal-title":"J. Gen. Physiol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"11193","DOI":"10.3390\/ijms231911193","article-title":"Neuro-inflammation modulation and post-traumatic brain injury lesions: from bench to bed-side","volume":"23","author":"Jacquens","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/PL00007970","article-title":"The dynamics of a neuronal culture of dissociated cortical neurons of neonatal rats","volume":"83","author":"Jimbo","year":"2000","journal-title":"Biol. Cybern."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.trsl.2022.08.014","article-title":"Inflammasome activation in traumatic brain injury and Alzheimer\u2019s disease","volume":"254","author":"Johnson","year":"2023","journal-title":"Transl. Res."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.tice.2019.09.005","article-title":"Role of pyridoxine in GABA synthesis and degradation in the hippocampus","volume":"61","author":"Jung","year":"2019","journal-title":"Tissue Cell"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1113\/jphysiol.1996.sp021606","article-title":"Ca(2+)-dependent inactivation of NMDA receptors: fast kinetics and high Ca2+ sensitivity in rat dorsal horn neurons","volume":"495","author":"Kyrozis","year":"1996","journal-title":"J. Physiol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1523\/JNEUROSCI.13-02-00674.1993","article-title":"Inactivation of NMDA channels in cultured hippocampal neurons by intracellular calcium","volume":"13","author":"Legendre","year":"1993","journal-title":"J. Neurosci."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"469","DOI":"10.3389\/fnins.2015.00469","article-title":"Chronic glutamate toxicity in neurodegenerative diseases-what is the evidence?","volume":"9","author":"Lewerenz","year":"2015","journal-title":"Front. Neurosci."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"e1005672","DOI":"10.1371\/journal.pcbi.1005672","article-title":"Recurrently connected and localized neuronal communities initiate coordinated spontaneous activity in neuronal networks","volume":"13","author":"Lonardoni","year":"2017","journal-title":"PLoS Comput. Biol."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1017\/S0007114511000407","article-title":"Vitamin B6: a challenging link between nutrition and inflammation in CVD","volume":"106","author":"Lotto","year":"2011","journal-title":"Br. J. Nutr."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3945\/jn.115.219378","article-title":"A vitamin B-6 antagonist from flaxseed perturbs amino acid metabolism in moderately vitamin B-6-deficient male rats","volume":"146","author":"Mayengbam","year":"2016","journal-title":"J. Nutr."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1080\/13550280590922757","article-title":"Cerebrospinal fluid from human immunodeficiency virus--infected individuals facilitates neurotoxicity by suppressing intracellular calcium recovery","volume":"11","author":"Meeker","year":"2005","journal-title":"J. Neurovirol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.expneurol.2015.09.012","article-title":"Novel p75 neurotrophin receptor ligand stabilizes neuronal calcium, preserves mitochondrial movement and protects against HIV associated neuropathogenesis","volume":"275","author":"Meeker","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1111\/nure.12014","article-title":"Mechanistic perspective on the relationship between pyridoxal 5\u2032-phosphate and inflammation","volume":"71","author":"Paul","year":"2013","journal-title":"Nutr. Rev."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"3341","DOI":"10.1073\/pnas.1515105113","article-title":"Network synchronization in hippocampal neurons","volume":"113","author":"Penn","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1038\/nrneurol.2010.17","article-title":"Microglia in neurodegenerative disease","volume":"6","author":"Perry","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"e25669","DOI":"10.7759\/cureus.25669","article-title":"Low serum pyridoxine levels worsen seizure control in adult epilepsy patients","volume":"14","author":"Rane","year":"2022","journal-title":"Cureus."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/j.biopsych.2021.11.012","article-title":"Role of inflammation in traumatic brain injury-associated risk for neuropsychiatric disorders: state of the evidence and where do we go from Here","volume":"91","author":"Risbrough","year":"2022","journal-title":"Biol. Psychiatry"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/j.ceca.2016.09.005","article-title":"Fast interaction between AMPA and NMDA receptors by intracellular calcium","volume":"60","author":"Rozov","year":"2016","journal-title":"Cell Calcium"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s12028-022-01579-z","article-title":"Association of serum pyridoxal phosphate levels with established status epilepticus","volume":"38","author":"Rubinos","year":"2022","journal-title":"Neurocrit. Care."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"105035","DOI":"10.1016\/j.neuint.2021.105035","article-title":"Resilience of network activity in preconditioned neurons exposed to \u2018stroke-in-a-dish\u2019 insults","volume":"146","author":"Tauskela","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"2169","DOI":"10.1016\/j.celrep.2017.07.082","article-title":"The deacetylase HDAC6 mediates endogenous Neuritic tau pathology","volume":"20","author":"Tseng","year":"2017","journal-title":"Cell Rep."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/nrn1327","article-title":"Homeostatic plasticity in the developing nervous system","volume":"5","author":"Turrigiano","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.mam.2016.08.001","article-title":"Inflammation, vitamin B6 and related pathways","volume":"53","author":"Ueland","year":"2017","journal-title":"Mol. Asp. Med."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1111\/j.1528-1167.2005.00298.x","article-title":"Brain inflammation in epilepsy: experimental and clinical evidence","volume":"46","author":"Vezzani","year":"2005","journal-title":"Epilepsia"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"e54478","DOI":"10.1371\/journal.pone.0054478","article-title":"Altered network communication following a neuroprotective drug treatment","volume":"8","author":"Vincent","year":"2013","journal-title":"PLoS One"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2011\/489470","article-title":"Mechanisms of GABAergic homeostatic plasticity","volume":"2011","author":"Wenner","year":"2011","journal-title":"Neural Plast."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"855701","DOI":"10.3389\/fimmu.2022.855701","article-title":"Neuroinflammation following traumatic brain injury: take it seriously or not","volume":"13","author":"Zheng","year":"2022","journal-title":"Front. Immunol."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1621349\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T00:10:44Z","timestamp":1750637444000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2025.1621349\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,23]]},"references-count":42,"alternative-id":["10.3389\/fnins.2025.1621349"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2025.1621349","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,23]]},"article-number":"1621349"}}