Neuronal localization of the GABA transporter GAT-3 in human cerebral cortex: A procedural artifact?

Melone, Marcello; Barbaresi, Paolo; Fattorini, Giorgia; Conti, Fiorenzo

doi:10.1016/j.jchemneu.2005.04.002

Cited by 24 publications

(14 citation statements)

References 49 publications

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“…More recently, we reported significant GAT-1 expression in oligodendrocytes and microglia (Fattorini et al, 2017(Fattorini et al, , 2020; Figure 2). In this connection, it is worth noting that GAT-3, a putative ''glial'' transporter (see Minelli et al, 1996 for the neocortex), also seems to be expressed in brainstem and cortical neurons, at least in certain experimental conditions (Clark et al, 1992;Melone et al, 2003Melone et al, , 2005Melone et al, , 2015, and that GAT-2, another putative ''glial'' transporter, is expressed in epithelial cells and, although at a very low level, also in neurons (Conti et al, 1999). It therefore seems that the era of ''neuronal'' and ''glial'' GABA transporters has finally come to a close.…”

Section: Discussionmentioning

confidence: 99%

A Reappraisal of GAT-1 Localization in Neocortex

Fattorini

Melone

Conti

2020

Front. Cell. Neurosci.

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γ-Aminobutyric acid (GABA) transporter (GAT)-1, the major GABA transporter in the brain, plays a key role in modulating GABA signaling and is involved in the pathophysiology of several neuropsychiatric diseases, including epilepsy. The original description of GAT-1 as a neuronal transporter has guided the interpretation of the findings of all physiological, pharmacological, genetic, or clinical studies. However, evidence published in the past few years, some of which is briefly reviewed herein, does not seem to be consistent with a neurocentric view of GAT-1 function and calls for more detailed analysis of its localization. We therefore performed a thorough systematic assessment of GAT-1 localization in neocortex and subcortical white matter. In line with earlier work, we found that GAT-1 was robustly expressed in axon terminals forming symmetric synapses and in astrocytic processes, whereas its astrocytic expression was more diffuse than expected and, even more surprisingly, immature and mature oligodendrocytes and microglial cells also expressed the transporter. These data indicate that the era of "neuronal" and "glial" GABA transporters has finally come to a close and provide a wider perspective from which to view GABA-mediated physiological phenomena. In addition, given the well-known involvement of astrocytes, oligodendrocytes, and microglial cells in physiological as well as pathological conditions, the demonstration of functional GAT-1 in these cells is expected to provide greater insight into the phenomena occurring in the diseased brain as well as to prompt a reassessment of earlier findings.

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Section: Discussionmentioning

confidence: 99%

A Reappraisal of GAT-1 Localization in Neocortex

Fattorini

Melone

Conti

2020

Front. Cell. Neurosci.

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“…Samples from 7 of the 13 cases have been used previously (Conti et al, 1998, 1999; Melone et al, 2004, 2005a, 2006). Cortical tissue used in this study was not located in the vicinity of the tumor: it was macroscopically normal tissue that had to be resected in order to reach deep-seated tumors or was included in “tactical lobectomies,” and showed no signs of edema.…”

Section: Methodsmentioning

confidence: 99%

“… 1 Drugs used in perisurgical prophylactic therapy . a–e Cases used in previous studies: a Conti et al (1998); b Conti et al (1999); c Melone et al (2004); d Melone et al (2005a); e Melone et al (2006) .…”

Section: Methodsmentioning

confidence: 99%

Cellular and Synaptic Localization of EAAT2a in Human Cerebral Cortex

Melone¹,

Bellesi²,

Ducati³

et al. 2011

Front. Neuroanat.

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We used light and electron microscopic immunocytochemical techniques to analyze the distribution, cellular and synaptic localization of EAAT2, the main glutamate transporter, in normal human neocortex. EAAT2a-immunoreactivity (ir) was in all layers and consisted of small neuropilar puncta and rare cells. In white matter EAAT2a+ cells were numerous. Electron microscopic studies showed that in gray matter ∼77% of immunoreactive elements were astrocytic processes, ∼14% axon terminals, ∼2.8% dendrites, whereas ∼5% were unidentifiable. In white matter, ∼81% were astrocytic processes, ∼17% were myelinated axons, and ∼2.0% were unidentified. EAAT2a-ir was never in microglial cells and oligodendrocytes. Pre-embedding electron microscopy showed that ∼67% of EAAT2a expressed at (or in the vicinity of) asymmetric synapses was in astrocytes, ∼17% in axon terminals, while ∼13% was both in astrocytes and in axons. Post-embedding electron microscopy studies showed that in astrocytic processes contacting asymmetric synapses and in axon terminals, gold particle density was ∼25.1 and ∼2.8 particles/μm2, respectively, and was concentrated in a membrane region extending for ∼300 nm from the active zone edge. Besides representing the first detailed description of EAAT2a in human cerebral cortex, these findings may contribute to understanding its role in the pathophysiology of neuropsychiatric diseases.

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“…When studying human samples, post-mortem proteolysis may complicate interpretation because the termini of EAAT1 and EAAT2 are rapidly proteolyzed ( 150 – 152 ). Post-mortem changes affect GAT3 more than GAT1 ( 153 ). It is a good idea to use additional methods, including in situ hybridization and Western blotting.…”

Section: Localization and Function – Numbers Mattermentioning

confidence: 99%

GABA and Glutamate Transporters in Brain

2013

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The mammalian genome contains four genes encoding GABA transporters (GAT1, slc6a1; GAT2, slc6a13; GAT3, slc6a11; BGT1, slc6a12) and five glutamate transporter genes (EAAT1, slc1a3; EAAT2, slc1a2; EAAT3, slc1a1; EAAT4, slc1a6; EAAT5, slc1a7). These transporters keep the extracellular levels of GABA and excitatory amino acids low and provide amino acids for metabolic purposes. The various transporters have different properties both with respect to their transport functions and with respect to their ability to act as ion channels. Further, they are differentially regulated. To understand the physiological roles of the individual transporter subtypes, it is necessary to obtain information on their distributions and expression levels. Quantitative data are important as the functional capacity is limited by the number of transporter molecules. The most important and most abundant transporters for removal of transmitter glutamate in the brain are EAAT2 (GLT-1) and EAAT1 (GLAST), while GAT1 and GAT3 are the major GABA transporters in the brain. EAAT3 (EAAC1) does not appear to play a role in signal transduction, but plays other roles. Due to their high uncoupled anion conductance, EAAT4 and EAAT5 seem to be acting more like inhibitory glutamate receptors than as glutamate transporters. GAT2 and BGT1 are primarily expressed in the liver and kidney, but are also found in the leptomeninges, while the levels in brain tissue proper are too low to have any impact on GABA removal, at least in normal young adult mice. The present review will provide summary of what is currently known and will also discuss some methodological pitfalls.

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Neuronal localization of the GABA transporter GAT-3 in human cerebral cortex: A procedural artifact?

Cited by 24 publications

References 49 publications

A Reappraisal of GAT-1 Localization in Neocortex

A Reappraisal of GAT-1 Localization in Neocortex

Cellular and Synaptic Localization of EAAT2a in Human Cerebral Cortex

GABA and Glutamate Transporters in Brain

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