Schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function. We sought to determine whether this diverse pathology could be linked to NMDA receptor (NMDAR) hypofunction, and thus used the serine racemase-null mutant mouse (SR −/− ), which has less than 10% of normal brain D-serine, an NMDAR coagonist. We found that D-serine was necessary for the maintenance of long-term potentiation in the adult hippocampal dentate gyrus and for full NMDAR activity on granule cells. SR −/− mice had reduced dendritic spines and hippocampal volume. These morphological changes were paralleled by diminished BDNF/Akt/mammalian target of rapamycin (mTOR) signaling and impaired performance on a traceconditioning memory task. Chronic D-serine treatment normalized the electrophysiological, neurochemical, and cognitive deficits in SR −/− mice. These results demonstrate that NMDAR hypofunction can reproduce the numerous hippocampal deficits associated with schizophrenia, which can be reversed by chronic peripheral D-serine treatment.miR-132 | MeCP2 | glycogen synthase 3 kinase | CREB S chizophrenia is a severe psychiatric disorder that affects 1% of the population worldwide (1). There are widespread morphological, neurochemical, and functional changes in the brain in schizophrenia that have been linked to its symptomatic features (2). For example, the hippocampus of patients with schizophrenia exhibits reduced dendritic spine density (3), atrophy (4), and impaired activation while performing cognitive tasks (5). The neuroplasticity deficits observed in schizophrenia could be caused by a constellation of factors.Impaired neurotrophic signaling could be one mechanism underlying these abnormalities. BDNF regulates a complex array of processes, including neurite outgrowth and spine density, by signaling through tropomyosin receptor kinase B (TrkB), its highaffinity receptor (6). In postmortem studies, BDNF mRNA and protein (7-9) levels, as well as TrkB mRNA (7, 10, 11) and protein (12), are reduced in subjects with schizophrenia. V-akt murine thymoma viral oncogene (Akt) is a kinase downstream of TrkB. Not only is the Akt1 isoform a putative schizophrenia risk gene (13), its expression (14, 15) and the amount of phosphorylated Akt (p-Akt) (16) in the dentate gyrus (DG) are reduced in schizophrenia.Aberrant microRNA (miR) processing might also be contributing to the pathophysiology of schizophrenia (17). These noncoding RNAs regulate neural plasticity by controlling the translation of target mRNA transcripts. Expression of the neuron-enriched miR-132 is reduced in schizophrenia (18); it regulates basal and activityinduced neurite outgrowth (19), and is up-regulated in vivo in response to external stimuli (20, 21). Importantly, both BDNF (22) and miR-132 (17) expression are increased by NMDAR receptor (NMDAR) activation.Pharmacologic and biochemical evidence has converged to support NMDAR hypofunct...

d-Serine, a co-agonist at the NMDA receptor (NMDAR), is synthesized from l-serine by the enzyme serine racemase (SR), which is heavily expressed in the forebrain. Although SR was originally reported to be localized exclusively to astrocytes, recent conditional knock out results demonstrate that little SR is expressed in forebrain astrocytes. As a consequence, the cellular location of its product, d-serine, in the brain is also uncertain. Immunocytochemistry now indicates that SR is expressed primarily in forebrain glutamatergic neurons with the remainder in GABAergic interneurons. We utilized SR deficient (SR–/–) mice, which have <15 % of normal d-serine levels, to validate and optimize a d-serine immunohistochemical method. Nearly all of the d-serine in neocortex and hippocampus (HP) is found in neurons, with virtually no d-serine co-localizing with two astrocyte markers. Interestingly, only a subset of the d-serine positive neurons contained SR in the neocortex and HP. Greater than half of the d-serine positive neurons were GABAergic interneurons, with a majority of these neurons containing parvalbumin and/or somatostatin. Only ∼25–40 % of interneurons expressed SR in the neocortex and HP. Finally, we demonstrate in human post-mortem neocortex that SR is found in both excitatory and inhibitory neurons, but not in S100β-containing astrocytes. In sum, these findings conclusively demonstrate that the majority of d-serine is both synthesized and stored in neurons. It will be important to determine the functional significance for the separation of synthesis and storage of d-serine in neurons, as well as the presence of this NMDAR co-agonist in GABAergic interneurons.

Background Little information is available about the geo-economic variations in demographics, management, and outcomes of patients with acute respiratory distress syndrome (ARDS). We aimed to characterise the effect of these geo-economic variations in patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE). Methods LUNG SAFE was done during 4 consecutive weeks in winter, 2014, in a convenience sample of 459 intensivecare units in 50 countries across six continents. Inclusion criteria were admission to a participating intensive-care unit (including transfers) within the enrolment window and receipt of invasive or non-invasive ventilation. One of the trial's secondary aims was to characterise variations in the demographics, management, and outcome of patients with ARDS. We used the 2016 World Bank countries classification to define three major geo-economic groupings, namely European high-income countries (Europe-High), high-income countries in the rest of the world (rWORLD-High), and middle-income countries (Middle). We compared patient outcomes across these three groupings. LUNG SAFE is registered with ClinicalTrials.gov, number NCT02010073. Findings Of the 2813 patients enrolled in LUNG SAFE who fulfilled ARDS criteria on day 1 or 2, 1521 (54%) were recruited from Europe-High, 746 (27%) from rWORLD-High, and 546 (19%) from Middle countries. We noted significant geographical variations in demographics, risk factors for ARDS, and comorbid diseases. The proportion of patients with severe ARDS or with ratios of the partial pressure of arterial oxygen (PaO 2) to the fractional concentration of oxygen in inspired air (F I O 2) less than 150 was significantly lower in rWORLD-High countries than in the two other regions. Use of prone positioning and neuromuscular blockade was significantly more common in Europe-High countries than in the other two regions. Adjusted duration of invasive mechanical ventilation and length of stay in the intensive-care unit were significantly shorter in patients in rWORLD-High countries than in Europe-High or Middle countries. High gross national income per person was associated with increased survival in ARDS; hospital survival was significantly lower in Middle countries than in Europe-High or rWORLD-High countries. Interpretation Important geo-economic differences exist in the severity, clinician recognition, and management of ARDS, and in patients' outcomes. Income per person and outcomes in ARDS are independently associated.