Astrocytes convert network excitation to tonic inhibition of neurons

<p>Abstract</p> <p>Background</p> <p>Glutamate and γ-aminobutyric acid (GABA) transporters play important roles in balancing excitatory and inhibitory signals in the brain. Increasing evidence suggest that they may act concertedly to regulate extracellular levels of the neurotransmitters.</p> <p>Results</p> <p>Here we present evidence that glutamate uptake-induced release of GABA from astrocytes has a direct impact on the excitability of pyramidal neurons in the hippocampus. We demonstrate that GABA, synthesized from the polyamine putrescine, is released from astrocytes by the reverse action of glial GABA transporter (GAT) subtypes GAT-2 or GAT-3. GABA release can be prevented by blocking glutamate uptake with the non-transportable inhibitor DHK, confirming that it is the glutamate transporter activity that triggers the reversal of GABA transporters, conceivably by elevating the intracellular Na⁺concentration in astrocytes. The released GABA significantly contributes to the tonic inhibition of neurons in a network activity-dependent manner. Blockade of the Glu/GABA exchange mechanism increases the duration of seizure-like events in the low-[Mg²⁺] <it>in vitro </it>model of epilepsy. Under <it>in vivo </it>conditions the increased GABA release modulates the power of gamma range oscillation in the CA1 region, suggesting that the Glu/GABA exchange mechanism is also functioning in the intact hippocampus under physiological conditions.</p> <p>Conclusions</p> <p>The results suggest the existence of a novel molecular mechanism by which astrocytes transform glutamat<it>ergic </it>excitation into GABA<it>ergic </it>inhibition providing an adjustable, <it>in situ </it>negative feedback on the excitability of neurons.</p

Glutamate Uptake Triggers Transporter-Mediated GABA Release from Astrocytes

Background: Glutamate (Glu) and c-aminobutyric acid (GABA) transporters play important roles in regulating neuronal activity. Glu is removed from the extracellular space dominantly by glial transporters. In contrast, GABA is mainly taken up by neurons. However, the glial GABA transporter subtypes share their localization with the Glu transporters and their expression is confined to the same subpopulation of astrocytes, raising the possibility of cooperation between Glu and GABA transport processes. Methodology/Principal Findings: Here we used diverse biological models both in vitro and in vivo to explore the interplay between these processes. We found that removal of Glu by astrocytic transporters triggers an elevation in the extracellular level of GABA. This coupling between excitatory and inhibitory signaling was found to be independent of Glu receptor-mediated depolarization, external presence of Ca2+ and glutamate decarboxylase activity. It was abolished in the presence of non-transportable blockers of glial Glu or GABA transporters, suggesting that the concerted action of these transporters underlies the process. Conclusions/Significance: Our results suggest that activation of Glu transporters results in GABA release through reversal of glial GABA transporters. This transporter-mediated interplay represents a direct link between inhibitory and excitatory neurotransmission and may function as a negative feedback combating intense excitation in pathological conditions such as epilepsy or ischemia

An iconic language for the graphical representation of medical concepts

<p>Abstract</p> <p>Background</p> <p>Many medication errors are encountered in drug prescriptions, which would not occur if practitioners could remember the drug properties. They can refer to drug monographs to find these properties, however drug monographs are long and tedious to read during consultation. We propose a two-step approach for facilitating access to drug monographs. The first step, presented here, is the design of a graphical language, called VCM.</p> <p>Methods</p> <p>The VCM graphical language was designed using a small number of graphical primitives and combinatory rules. VCM was evaluated over 11 volunteer general practitioners to assess if the language is easy to learn, to understand and to use. Evaluators were asked to register their VCM training time, to indicate the meaning of VCM icons and sentences, and to answer clinical questions related to randomly generated drug monograph-like documents, supplied in text or VCM format.</p> <p>Results</p> <p>VCM can represent the various signs, diseases, physiological states, life habits, drugs and tests described in drug monographs. Grammatical rules make it possible to generate many icons by combining a small number of primitives and reusing simple icons to build more complex ones. Icons can be organized into simple sentences to express drug recommendations. Evaluation showed that VCM was learnt in 2 to 7 hours, that physicians understood 89% of the tested VCM icons, and that they answered correctly to 94% of questions using VCM (versus 88% using text, <it>p </it>= 0.003) and 1.8 times faster (<it>p </it>< 0.001).</p> <p>Conclusion</p> <p>VCM can be learnt in a few hours and appears to be easy to read. It can now be used in a second step: the design of graphical interfaces facilitating access to drug monographs. It could also be used for broader applications, including the design of interfaces for consulting other types of medical document or medical data, or, very simply, to enrich medical texts.</p

Extensive astrocyte synchronization advances neuronal coupling in slow wave activity in vivo

Slow wave activity (SWA) is a characteristic brain oscillation in sleep and quiet wakefulness. Although the cell types contributing to SWA genesis are not yet identified, the principal role of neurons in the emergence of this essential cognitive mechanism has not been questioned. To address the possibility of astrocytic involvement in SWA, we used a transgenic rat line expressing a calcium sensitive fluorescent protein in both astrocytes and interneurons and simultaneously imaged astrocytic and neuronal activity in vivo. Here we demonstrate, for the first time, that the astrocyte network display synchronized recurrent activity in vivo coupled to UP states measured by field recording and neuronal calcium imaging. Furthermore, we present evidence that extensive synchronization of the astrocytic network precedes the spatial build-up of neuronal synchronization. The earlier extensive recruitment of astrocytes in the synchronized activity is reinforced by the observation that neurons surrounded by active astrocytes are more likely to join SWA, suggesting causality. Further supporting this notion, we demonstrate that blockade of astrocytic gap junctional communication or inhibition of astrocytic Ca2+ transients reduces the ratio of both astrocytes and neurons involved in SWA. These in vivo findings conclusively suggest a causal role of the astrocytic syncytium in SWA generation

Polymorphisms in the MASP1 gene are associated with serum levels of MASP-1, MASP-3, and MAp44

MASP-1 is the first protein in the activation of the lectin pathway and MASP-1 is, like its isoforms MASP-3 and MAp44, encoded by the MASP1 gene. Our aim was to explore associations between polymorphisms in MASP1 and corresponding concentrations of MASP-1, MASP-3, and MAp44 in plasma as well as the genetic contribution to the equilibrium between the three proteins.Fifteen SNPs were genotyped in the MASP1 gene in 350 blood donors. Corresponding plasma concentrations of MASP-1, MASP-3, and MAp44 were measured.A total of 10 different SNPs showed associations with the concentration of one or some of the three proteins (rs113938200, rs190590338, rs35089177, rs3774275, rs67143992, rs698090, rs72549154, rs72549254, rs75284004, rs7625133), and several of these were in strong linkage. SNPs located in the mutually exclusive splice region had opposite effects on the protein concentrations. Being e.g. homozygote for the minor allele of rs3774275 was associated with an increase in median concentration of 13% in MASP-1(P=0.03), 29% in MAp44 (P<0.001), and a decrease in MASP-3 of 26% (P<0.001) compared to homozygosis for the major allele. Heterozygosis of rs113938200 (p.Asn368Asp in MAp44) was associated with a reduced MAp44 concentration of 61% (P=0.005). Rs190590338 located in the promoter region was associated in the heterozygote form with an increased MASP-1 concentration of 35% (P = 0.002). A multivariate linear regression model including sex, age, M- and H-ficolin, MBL, and the 15 SNPs explained 20-48% of the variation in the concentration of the three proteins and the SNPs investigated contributed with the most explanatory power (12-23%).The present study described 10 SNPs, which were associated with the concentration of one or some of the three proteins originating from the MASP1 gene and in a multivariate model it was shown that the SNPs contributed with the most explanatory power to the protein concentrations