{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n D‐amino acid oxidase (DAO) is a flavoprotein enzyme that plays a crucial role in central nervous system physiology by catalyzing the oxidative deamination of D‐serine, a key endogenous co‐agonist at N‐methyl‐D‐aspartate (NMDA) receptors. By degrading D‐serine, DAO critically modulates NMDA receptor activation and thereby influences excitatory neurotransmission, synaptic plasticity, and neurotoxicity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Alternative splicing events—such as the skipping of an exon in DAO—have been reported to reduce its metabolic capacity, potentially leading to altered D‐serine levels and impacting NMDA receptor function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In postmortem studies, elevated DAO activity and mRNA expression have been documented in specific brain regions in schizophrenia, suggesting that dysregulation of DAO‐mediated catabolism of D‐serine might contribute to NMDA receptor hypofunction, a pathway implicated in the pathogenesis of psychiatric disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Genetic association studies have further linked polymorphisms at the DAO locus with schizophrenia and related affective symptoms, bolstering the notion that genetic variations influencing DAO activity can modulate D‐serine availability and, in turn, NMDA receptor–mediated neurotransmission."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Experimental investigations using DAO knockout mice have demonstrated enhanced spatial and olfactory recognition memory, along with increased anxiety‐like behaviors, thereby supporting the concept that limited DAO activity and the resultant elevation in D‐serine may enhance certain aspects of cognitive performance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " At the cellular level, studies in human-derived cells have elucidated that distinct cellular compartments regulate DAO turnover via different proteolytic pathways, and that specific missense mutations in the DAO gene can alter both its kinetic properties and FAD binding, ultimately affecting D‐serine catabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings indicate that DAO is a key regulatory enzyme in D‐serine metabolism whose functional integrity is essential for normal NMDA receptor signaling. Aberrations in DAO expression, alternative splicing, or genetic variation may lead to imbalances in D‐serine levels, thereby contributing to NMDA receptor hypofunction and increasing susceptibility to neuropsychiatric conditions such as schizophrenia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": " \n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Louise Verrall, Mary Walker, Nancy Rawlings, et al. 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