Glial transporters for glutamate, glycine, and GABA III. Glycine transporters

Gadea, Ana; López-Colomé, Ana Marı́a

doi:10.1002/jnr.1069

Cited by 49 publications

(23 citation statements)

References 57 publications

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“…We modified the metabolic pathways to include compartmentalization of NADH between the cytosol and mitochondria. To do so, we developed a very simple model of mitochondrial respiration and added NADH malate-aspartate shuttles between the cytosol and mitochondria, drawing inspiration from a model by [58]. Finally, the model is driven by external input modeled as a global excitatory presynaptic activity and coordinated increase of the cerebral blood flow.…”

Section: Resultsmentioning

confidence: 99%

Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

et al. 2015

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Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain’s metabolic interactions. Our model integrates three modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging.

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Section: Resultsmentioning

confidence: 99%

Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

et al. 2015

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“…GlyT1 has emerged as a promising pharmacological target to treat cognitive dysfunctions in schizophrenia or to enhance general cognition function (Atkinson et al, 2001; Gadea and Lopez-Colome, 2001; Chen et al, 2003). Following the discovery of neuronal GlyT1 (Cubelos et al, 2005), the cell-type specific roles of GlyT1 (neuronal vs. glial) in modifying cognitive functions have not been addressed.…”

Section: Discussionmentioning

confidence: 99%

Altered mnemonic functions and resistance to N-METHYL-d-Aspartate receptor antagonism by forebrain conditional knockout of glycine transporter 1

et al. 2009

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Converging evidence from pharmacological and molecular studies has led to the suggestion that inhibition of glycine transporter 1 (GlyT1) constitutes an effective means to boost N-methyl-Daspartate receptor (NMDAR) activity by increasing the extra-cellular concentration of glycine in the vicinity of glutamatergic synapses. However, the precise extent and limitation of this approach to alter cognitive function, and therefore its potential as a treatment strategy against psychiatric conditions marked by cognitive impairments, remains to be fully examined. Here, we generated mutant mice lacking GlyT1 in the entire forebrain including neurons and glia. This conditional knockout system allows a more precise examination of GlyT1 down-regulation in the brain on behaviour and cognition. The mutation was highly effective in attenuating the motor-stimulating effect of acute NMDAR blockade by phencyclidine, although no appreciable elevation in NMDARmediated EPSC was observed in the hippocampus. Enhanced cognitive performance was observed in spatial working memory and object recognition memory while spatial reference memory and associative learning remained unaltered. These findings provide further credence for the potential cognitive enhancing effects of brain GlyT1 inhibition. At the same time, they indicated potential phenotypic differences when compared with other constitutive and conditional GlyT1 knockout lines, and highlighted the possibility of a functional divergence between the neuronal and glia subpopulations of GlyT1 in the regulation of learning and memory processes. The relevance of this distinction to the design of future GlyT1 blockers as therapeutic tools in the treatment of cognitive disorders remains to be further investigated.

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“…1991). Ca 2+ ‐independent release has been ascribed to glial Gly transporters (reviewed in Gadea and López‐Colomé 2001a), which have a stoichiometry of 2/Na + /Cl – /Gly, versus neuronal ones, with 3Na + /Cl – /Gly stoichiometry (Roux and Supplisson 2000).…”

mentioning

confidence: 99%

“…Two different glycine transporters have been cloned: GLYT1, with three isoforms derived from alternative splicing and/or promoter usage termed GLYT1a, GLYT1b and GLYT1c, inhibited by sarcosine and expressed in glial cells throughout the CNS, and GLYT2, expressed predominantly in brain stem and spinal cord, where glycine is considered the major inhibitory neurotransmitter (reviewed in Gadea and López‐Colomé 2001a). GLYT1 thus, shows the expected properties for controlling extracellular Gly concentration, tonically modulating NMDA receptors, whereas GLYT2 could function in Gly accumulation at inhibitory glycinergic synapses.…”

mentioning

confidence: 99%

Role of Ca²⁺ and calmodulin‐dependent enzymes in the regulation of glycine transport in Müller glia

Gadea

López

Hernández‐Cruz

et al. 2002

Journal of Neurochemistry

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Glycine (Gly) is considered an obligatory co-agonist at NMDA receptors. Mü ller glia from the retina harbor functional NMDA receptors, as well as low and high affinity Gly transporters, the later identified as GLYT1. We here studied the regulation of Gly transport in primary cultures of Mü ller glia, as this process could contribute to the modulation of NMDA receptor activity at glutamatergic synapses in the retina. We demonstrate that neither glutamate stimulation nor the activation or inhibition of protein kinases A or C modify transport. In order to assess a function for Ca 2+

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Glial transporters for glutamate, glycine, and GABA III. Glycine transporters

Cited by 49 publications

References 57 publications

Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

Altered mnemonic functions and resistance to N-METHYL-d-Aspartate receptor antagonism by forebrain conditional knockout of glycine transporter 1

Role of Ca²⁺ and calmodulin‐dependent enzymes in the regulation of glycine transport in Müller glia

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Glial transporters for glutamate, glycine, and GABA III. Glycine transporters

Cited by 49 publications

References 57 publications

Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

Multi-timescale Modeling of Activity-Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

Altered mnemonic functions and resistance to N-METHYL-d-Aspartate receptor antagonism by forebrain conditional knockout of glycine transporter 1

Role of Ca2+ and calmodulin‐dependent enzymes in the regulation of glycine transport in Müller glia

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Role of Ca²⁺ and calmodulin‐dependent enzymes in the regulation of glycine transport in Müller glia