Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
Cells ; 9(7)2020 07 13.
Article in English | MEDLINE | ID: mdl-32668809

ABSTRACT

GABA signaling is involved in a wide range of neuronal functions, such as synchronization of action potential firing, synaptic plasticity and neuronal development. Sustained GABA signaling requires efficient mechanisms for the replenishment of the neurotransmitter pool of GABA. The prevailing theory is that exocytotically released GABA may be transported into perisynaptic astroglia and converted to glutamine, which is then shuttled back to the neurons for resynthesis of GABA-i.e., the glutamate/GABA-glutamine (GGG) cycle. However, an unequivocal demonstration of astroglia-to-nerve terminal transport of glutamine and the contribution of astroglia-derived glutamine to neurotransmitter GABA synthesis is lacking. By genetic inactivation of the amino acid transporter Solute carrier 38 member a1 (Slc38a1)-which is enriched on parvalbumin+ GABAergic neurons-and by intraperitoneal injection of radiolabeled acetate (which is metabolized to glutamine in astroglial cells), we show that Slc38a1 mediates import of astroglia-derived glutamine into GABAergic neurons for synthesis of GABA. In brain slices, we demonstrate the role of Slc38a1 for the uptake of glutamine specifically into GABAergic nerve terminals for the synthesis of GABA depending on demand and glutamine supply. Thus, while leaving room for other pathways, our study demonstrates a key role of Slc38a1 for newly formed GABA, in harmony with the existence of a GGG cycle.


Subject(s)
Amino Acid Transport System A/metabolism , Astrocytes/metabolism , Interneurons/metabolism , Neurotransmitter Agents/metabolism , gamma-Aminobutyric Acid/biosynthesis , Acetates/metabolism , Animals , Glutamine/metabolism , Mice , Models, Biological , Synapses/metabolism
2.
Cereb Cortex ; 29(12): 5166-5179, 2019 12 17.
Article in English | MEDLINE | ID: mdl-31050701

ABSTRACT

GABA signaling sustains fundamental brain functions, from nervous system development to the synchronization of population activity and synaptic plasticity. Despite these pivotal features, molecular determinants underscoring the rapid and cell-autonomous replenishment of the vesicular neurotransmitter GABA and its impact on synaptic plasticity remain elusive. Here, we show that genetic disruption of the glutamine transporter Slc38a1 in mice hampers GABA synthesis, modifies synaptic vesicle morphology in GABAergic presynapses and impairs critical period plasticity. We demonstrate that Slc38a1-mediated glutamine transport regulates vesicular GABA content, induces high-frequency membrane oscillations and shapes cortical processing and plasticity. Taken together, this work shows that Slc38a1 is not merely a transporter accumulating glutamine for metabolic purposes, but a key component regulating several neuronal functions.


Subject(s)
Amino Acid Transport System A/metabolism , Brain/physiology , GABAergic Neurons/physiology , Neuronal Plasticity/physiology , Synaptic Transmission/physiology , Animals , Mice
3.
J Comp Neurol ; 480(3): 264-80, 2004 Dec 13.
Article in English | MEDLINE | ID: mdl-15515175

ABSTRACT

Three closely related proteins transport glutamate into synaptic vesicles for release by exocytosis. Complementary patterns of expression in glutamatergic terminals have been reported for VGLUT1 and VGLUT2. VGLUT3 shows expression by many cells not considered to be glutamatergic. Here we describe the changes in VGLUT expression that occur during development. VGLUT1 expression increases gradually after birth and eventually predominates over the other isoforms in telencephalic regions. Expressed at high levels shortly after birth, VGLUT2 declines with age in multiple regions, in the cerebellum by 14-fold. In contrast, Coexpression of the two isoforms occurs transiently during development as well as permanently in a restricted subset of glutamatergic terminals in the adult. VGLUT3 is transiently expressed at high levels by select neuronal populations, including terminals in the cerebellar nuclei, scattered neurons in the cortex, and progenitor-like cells, implicating exocytotic glutamate release in morphogenesis and development. VGLUT3 also colocalizes extensively during development with the neuronal vesicular monoamine transporter VMAT2, with the vesicular acetylcholine transporter VAChT, and with the vesicular gamma-aminobutyric acid transporter VGAT. Such coexpression occurs particularly at some specific developmental stages and is restricted to certain sets of cells. In skeletal muscle, VGLUT3 localizes to granular organelles in the axon terminal as well as in the muscle sarcoplasm. The results suggest novel mechanisms and roles for regulated transmitter release.


Subject(s)
Amino Acid Transport System X-AG/metabolism , Gene Expression Regulation, Developmental/physiology , Glutamic Acid/metabolism , Prosencephalon/metabolism , Synaptic Vesicles/metabolism , Vesicular Transport Proteins/metabolism , Amino Acid Transport System X-AG/genetics , Amino Acid Transport Systems, Acidic/genetics , Amino Acid Transport Systems, Acidic/metabolism , Animals , Astrocytes/cytology , Astrocytes/metabolism , Cells, Cultured , Exocytosis/physiology , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Mice , Mice, Inbred C57BL , Morphogenesis/genetics , Neurons/cytology , Neurons/metabolism , Neurotransmitter Agents/metabolism , Prosencephalon/cytology , Prosencephalon/embryology , Protein Isoforms , Rats , Stem Cells/cytology , Stem Cells/metabolism , Synaptic Vesicles/genetics , Tissue Distribution , Up-Regulation , Vesicular Glutamate Transport Protein 1 , Vesicular Glutamate Transport Protein 2 , Vesicular Glutamate Transport Proteins , Vesicular Transport Proteins/genetics
4.
Science ; 304(5678): 1815-9, 2004 Jun 18.
Article in English | MEDLINE | ID: mdl-15118123

ABSTRACT

Vesicular glutamate transporters (VGLUTs) 1 and 2 show a mutually exclusive distribution in the adult brain that suggests specialization for synapses with different properties of release. Consistent with this distribution, inactivation of the VGLUT1 gene silenced a subset of excitatory neurons in the adult. However, the same cell populations exhibited VGLUT1-independent transmission early in life. Developing hippocampal neurons transiently coexpressed VGLUT2 and VGLUT1 at distinct synaptic sites with different short-term plasticity. The loss of VGLUT1 also reduced the reserve pool of synaptic vesicles. Thus, VGLUT1 plays an unanticipated role in membrane trafficking at the nerve terminal.


Subject(s)
Brain/metabolism , Carrier Proteins/metabolism , Membrane Transport Proteins , Neurons/metabolism , Synapses/metabolism , Synaptic Transmission , Synaptic Vesicles/metabolism , Vesicular Transport Proteins , Animals , Animals, Newborn , Brain/cytology , Carrier Proteins/genetics , Cell Membrane/physiology , Cells, Cultured , Cerebellum/metabolism , Cerebellum/ultrastructure , Excitatory Postsynaptic Potentials , Glutamic Acid/metabolism , Hippocampus/cytology , Hippocampus/metabolism , Hippocampus/ultrastructure , In Situ Hybridization , Mice , Mice, Knockout , Nerve Tissue Proteins/metabolism , Neurons/physiology , Patch-Clamp Techniques , Purkinje Cells/physiology , Pyramidal Cells/metabolism , Synapses/ultrastructure , Synaptic Vesicles/physiology , Vesicular Glutamate Transport Protein 1 , Vesicular Glutamate Transport Protein 2
5.
J Neurosci ; 24(21): 4978-88, 2004 May 26.
Article in English | MEDLINE | ID: mdl-15163690

ABSTRACT

Recent studies implicate dendritic endocannabinoid release from subsynaptic dendrites and subsequent inhibition of neurotransmitter release from nerve terminals as a means of retrograde signaling in multiple brain regions. Here we show that type 1 cannabinoid receptor-mediated endocannabinoid signaling is not involved in the retrograde control of synaptic efficacy at inhibitory synapses between fast-spiking interneurons and pyramidal cells in layer 2/3 of the neocortex. Vesicular neurotransmitter transporters, such as vesicular glutamate transporters (VGLUTs) 1 and 2, are localized to presynaptic terminals and accumulate neurotransmitters into synaptic vesicles. A third subtype of VGLUTs (VGLUT3) was recently identified and found localized to dendrites of various cell types. We demonstrate, using multiple immunofluorescence labeling and confocal laser-scanning microscopy, that VGLUT3-like immunoreactivity is present in dendrites of layer 2/3 pyramidal neurons in the rat neocortex. Electron microscopy analysis confirmed that VGLUT3-like labeling is localized to vesicular structures, which show a tendency to accumulate in close proximity to postsynaptic specializations in dendritic shafts of pyramidal cells. Dual whole-cell recordings revealed that retrograde signaling between fast-spiking interneurons and pyramidal cells was enhanced under conditions of maximal efficacy of VGLUT3-mediated glutamate uptake, whereas it was reduced when glutamate uptake was inhibited by incrementing concentrations of the nonselective VGLUT inhibitor Evans blue (0.5-5.0 microm) or intracellular Cl- concentrations (4-145 mm). Our results present further evidence that dendritic vesicular glutamate release, controlled by novel VGLUT isoforms, provides fast negative feedback at inhibitory neocortical synapses, and demonstrate that glutamate can act as a retrograde messenger in the CNS.


Subject(s)
Amino Acid Transport Systems, Acidic/metabolism , Neocortex/physiology , Receptors, Cannabinoid/metabolism , Synapses/physiology , Animals , Dendrites/physiology , Dendrites/ultrastructure , Interneurons/metabolism , Neocortex/ultrastructure , Patch-Clamp Techniques , Pyramidal Cells/metabolism , Pyramidal Cells/ultrastructure , Rats , Rats, Sprague-Dawley , Synapses/ultrastructure , Vesicular Glutamate Transport Proteins
6.
Proc Natl Acad Sci U S A ; 99(22): 14488-93, 2002 Oct 29.
Article in English | MEDLINE | ID: mdl-12388773

ABSTRACT

Quantal release of the principal excitatory neurotransmitter glutamate requires a mechanism for its transport into secretory vesicles. Within the brain, the complementary expression of vesicular glutamate transporters (VGLUTs) 1 and 2 accounts for the release of glutamate by all known excitatory neurons. We now report the identification of VGLUT3 and its expression by many cells generally considered to release a classical transmitter with properties very different from glutamate. Remarkably, subpopulations of inhibitory neurons as well as cholinergic interneurons, monoamine neurons, and glia express VGLUT3. The dendritic expression of VGLUT3 by particular neurons also indicates the potential for retrograde synaptic signaling. The distribution and subcellular location of VGLUT3 thus suggest novel modes of signaling by glutamate.


Subject(s)
Amino Acid Transport Systems, Acidic/metabolism , Dendrites/metabolism , Glutamic Acid/metabolism , Signal Transduction , Amino Acid Transport Systems, Acidic/genetics , Animals , Brain/metabolism , Brain/pathology , Cell Membrane/metabolism , Humans , Hydrogen-Ion Concentration , Kidney/metabolism , Kidney/pathology , Liver/metabolism , Liver/pathology , Male , PC12 Cells , Rats , Tissue Distribution , Vesicular Glutamate Transport Proteins
SELECTION OF CITATIONS
SEARCH DETAIL
...