SummaryLysophosphatidic acid (LPA) is a synaptic phospholipid, which regulates cortical excitation/inhibition (E/I) balance and controls sensory information processing in mice and man. Altered synaptic LPA signaling was shown to be associated with psychiatric disorders. Here, we show that the LPA-synthesizing enzyme autotaxin (ATX) is expressed in the astrocytic compartment of excitatory synapses and modulates glutamatergic transmission. In astrocytes, ATX is sorted toward fine astrocytic processes and transported to excitatory but not inhibitory synapses. This ATX sorting, as well as the enzymatic activity of astrocyte-derived ATX are dynamically regulated by neuronal activity via astrocytic glutamate receptors. Pharmacological and genetic ATX inhibition both rescued schizophrenia-related hyperexcitability syndromes caused by altered bioactive lipid signaling in two genetic mouse models for psychiatric disorders. Interestingly, ATX inhibition did not affect naive animals. However, as our data suggested that pharmacological ATX inhibition is a general method to reverse cortical excitability, we applied ATX inhibition in a ketamine model of schizophrenia and rescued thereby the electrophysiological and behavioral schizophrenia-like phenotype. Our data show that astrocytic ATX is a novel modulator of glutamatergic transmission and that targeting ATX might be a versatile strategy for a novel drug therapy to treat cortical hyperexcitability in psychiatric disorders.

Alterations in dendritic spine numbers are linked to deficits in learning and memory. While we previously revealed that postsynaptic plasticity-related gene 1 (PRG-1) controls lysophosphatidic acid (LPA) signaling at glutamatergic synapses via presynaptic LPA receptors, we now show that PRG-1 also affects spine density and synaptic plasticity in a cell-autonomous fashion via protein phosphatase 2A (PP2A)/β1-integrin activation. PRG-1 deficiency reduces spine numbers and β1-integrin activation, alters long-term potentiation (LTP), and impairs spatial memory. The intracellular PRG-1 C terminus interacts in an LPA-dependent fashion with PP2A, thus modulating its phosphatase activity at the postsynaptic density. This results in recruitment of adhesome components src, paxillin, and talin to lipid rafts and ultimately in activation of β1-integrins. Consistent with these findings, activation of PP2A with FTY720 rescues defects in spine density and LTP of PRG-1-deficient animals. These results disclose a mechanism by which bioactive lipid signaling via PRG-1 could affect synaptic plasticity and memory formation.

Background: Whether all types of inhaled corticosteroids (ICSs) would increase the pneumonia risk in patients with chronic obstructive pulmonary disease (COPD) remains controversial. We aimed to assess the association between ICSs treatment and pneumonia risk in COPD patients, and the impact of medication details and baseline characteristics of patients on the association.Methods: Four databases (PubMed, Embase, Cochrane Library, and Clinical Trials.gov) were searched to identify eligible randomized controlled trials (RCTs) comparing ICSs treatment with non-ICSs treatment on the pneumonia risk in COPD patients. Pooled results were calculated using Peto odds ratios (Peto ORs) with corresponding 95% confidence intervals (CIs).Results: A total of 59 RCTs enrolling 103,477 patients were analyzed. All types of ICSs significantly increased the pneumonia risk (Peto OR, 1.43; 95% CI, 1.34–1.53). Subgroup analysis showed that there was a dose-response relationship between ICSs treatment and pneumonia risk (low-dose: Peto OR, 1.33; 95% CI, 1.22–1.45; medium-dose: Peto OR, 1.50; 95% CI, 1.28–1.76; and high-dose: Peto OR, 1.64; 95% CI, 1.45–1.85). Subgroup analyses based on treatment durations and baseline characteristics (severity, age, and body mass index) of patients were consistant with the above results. Subgroup analysis based on severity of pneumonia showed that fluticasone (Peto OR, 1.75; 95% CI, 1.44–2.14) increased the risk of serious pneumonia, while budesonide and beclomethasone did not.Conclusions: ICSs treatment significantly increased the risk of pneumonia in COPD patients. There was a dose-response relationship between ICSs treatment and pneumonia risk. The pneumonia risk was related with COPD severity.

Background We aimed to assess the association between inhaled corticosteroids (ICSs) and the risk of upper respiratory tract infection (URTI) in patients with chronic obstructive pulmonary disease (COPD). Methods PubMed, Embase, Cochrane Library and Clinical Trials.gov were searched from inception to October 2019. Randomized controlled trials (RCTs) of any ICSs vs control for COPD with reporting of URTI as an adverse event were included. The study was registered with PROSPERO prospectively (#CRD42020153134). Results Seventeen RCTs (20,478 patients) were included. ICSs significantly increased the risk of URTI in COPD patients (RR, 1.13; 95% CI 1.03–1.24; P = 0.01; heterogeneity: I2 = 7%). Futher subgroup analyses suggested that short-term use of ICSs increased the risk of URTI (RR, 1.29; 95% CI 1.06–1.56; P = 0.01; heterogeneity: I2 = 14%) but not for long-term use (RR, 1.08; 95% CI 0.97–1.2; P = 0.14; heterogeneity: I2 = 0%). Short-term use of high-dose fluticasone increased the risk of URTI (RR, 1.33; 95% CI 1.03–1.71; P = 0.03; heterogeneity: I2 = 0%) but not for long-term use (RR, 1.12; 95% CI 0.97–1.29; P = 0.13; heterogeneity: I2 = 50%). Medium-dose (RR, 0.97; 95% CI 0.71–1.32; P = 0.84; heterogeneity: I2 = 0%) and low-dose (RR, 1.39; 95% CI 0.92–2.1; P = 0.12; heterogeneity: I2 = 30%) fluticasone did not increase the risk of URTI regardless of duration. Neither mometasone (RR, 1.05; 95% CI 0.87–1.26; P = 0.61; heterogeneity: I2 = 0%) nor budesonide (RR, 1.08; 95% CI 0.77–1.5; P = 0.67; heterogeneity: I2 = 46%) increased the risk of URTI, regardless of dosage or duration. Conclusions Long-term use of ICSs does not increase the risk of URTI in patients with COPD. Short-term use of high-dose fluticasone increases the risk of URTI in patients with COPD, but not mometasone or budesonide.

d-Tubocurarine has been used for many years in the study of the physiology of neuromuscular transmission as an agent to immobilize isolated nervemuscle preparations. It is generally agreed that d-tubocurarine does not have any effect of the presynaptic event of junctional transmission since the experiment of DALE et al. (1936) which showed that d-tubocurarine paralysed skeletal muscles without inhibition of the release of acetylcholine (ACh) from motor nerve endings.This concept, however, is challenged by STANDAERT (1964) basing on the evidence that the post-tetanic antidromic discharges in motor nerves were abolished by d-tubocurarine at doses much smaller than that needed for the blockage of neuromuscular transmission.On the other hand, BEANI et al. (1964) claimed to have demonstrated that d-tubocurarine inhibits the release of ACh from motor nerve endings under certain conditions using diisopropylphosphorofluoridate as anticholinesterase agent. They suggested that, in the curarized preparation, the presynaptic effect might be a contributory factor in Wedensky inhibition.In the view that many of conclusions concerning the physiology of motor nerve endings, especially on the problem of ACh stores and release, have been drawn out from experiments using curarized preparations and that there exists some contradictory results, it was felt necessary to repeat the experiment of BEANI et al. (1964) and to settle whether or not d-tubocurarine inhibits the release of ACh from the motor nerve endings. Some electrophysiological experiments were also done in order to see whether d-tubocurarine affects the presynaptic events of the neuromuscular transmission. METHODSGuinea pig diaphragms for estimation of ACh. All the experiments for the study of