scholarly journals Astrocytic striatal GABA transporter activity governs dopamine release and shows maladaptive downregulation in early parkinsonism

2019 ◽  
Author(s):  
Bradley M. Roberts ◽  
Natalie M. Doig ◽  
Katherine R. Brimblecombe ◽  
Emanuel F. Lopes ◽  
Ruth E. Siddorn ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tonic Inhibition ◽  
Gaba Uptake ◽  
Projection Neurons ◽  
List Type ◽  
Dorsolateral Striatum ◽  
Gaba Transporters ◽  
Gaba Inhibition ◽  
Da Release ◽  
Accumbens Core

SummaryStriatal dopamine (DA) is critical for action and learning. Recent data show DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be governed by plasma membrane GABA uptake transporters (GATs) on astrocytes. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs were downregulated and tonic GABAergic inhibition of DA release augmented, with corresponding attenuation of GABA co-release from dopaminergic axons. These data define previously unappreciated and important roles for GATs and astrocytes in determining DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.HighlightsGABA transporters set the level of GABA inhibition of DA output in dorsal striatumAstrocytes facilitate DA release levels by limiting tonic GABA inhibitionTonic inhibition of DA release is augmented in a mouse model of early parkinsonismDA and GABA co-release are reduced in a mouse model of early parkinsonism

scholarly journals GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Bradley M. Roberts ◽  
Natalie M. Doig ◽  
Katherine R. Brimblecombe ◽  
Emanuel F. Lopes ◽  
Ruth E. Siddorn ◽  
...  
Keyword(s):  
Dorsal Striatum ◽  
Gaba Uptake ◽  
Projection Neurons ◽  
Nucleus Accumbens Core ◽  
Dorsolateral Striatum ◽  
Striatal Projection Neurons ◽  
Maladaptive Plasticity ◽  
Uptake Transporters ◽  
Da Release ◽  
Accumbens Core

Abstract Striatal dopamine (DA) is critical for action and learning. Recent data show that DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be determined by plasma membrane GABA uptake transporters (GATs) located on astrocytes and neurons. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs are downregulated, tonic GABAergic inhibition of DA release augmented, and nigrostriatal GABA co-release attenuated. These data define previously unappreciated and important roles for GATs and astrocytes in supporting DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.

scholarly journals Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Nicolas X Tritsch ◽  
Won-Jong Oh ◽  
Chenghua Gu ◽  
Bernardo L Sabatini
Keyword(s):  
Dopaminergic Neurons ◽  
De Novo ◽  
Dopamine Neurons ◽  
Gaba Uptake ◽  
Projection Neurons ◽  
Dependent Manner ◽  
Gaba Transporters ◽  
Midbrain Dopamine ◽  
Nigrostriatal Dopamine Neurons ◽  
Midbrain Dopamine Neurons

Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors.

scholarly journals 15 A novel CD28 humanized mouse model for efficacy assessment of CD28-targeting therapies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A15-A15
Author(s):  
Fabiane Sônego ◽  
Gaelle Martin ◽  
Chloé Beuraud ◽  
Audrey Beringer ◽  
Yacine Cherifi ◽  
...  
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
Mouse Model ◽  
Cytokine Production ◽  
List Type ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Efficacy Assessment ◽  
Human And Mouse ◽  
Stimulation Of

BackgroundImmuno-intervention through targeting of activating and inhibitory immune checkpoints (ICP), has shown promising results in the clinic over the last years. To facilitate these researches, mouse models expressing humanized ICP instead of their mouse counterparts were developed. Herein, we describe a novel CD28 humanized mouse model (hCD28 model), designed to test compounds targeting human CD28 (hCD28).MethodsHuman and mouse CD28 (mCD28) have different signalling responses, with hCD28 being known for inducing higher levels of pro-inflammatory cytokines upon stimulation with ligands/superagonists. This can be explained by the expression of CD28i, a hCD28 amplifier isoform which is not found in mouse. Additionally, evidences suggested that the different signalling between human and mCD28 relies on one amino acid change in the intracellular domain (ICD).1 Because the hCD28 model was developed to assess hCD28-targeting therapeutics, we decided to keep the expression of both canonical and CD28i isoforms to avoid undermining the biological effects of the testing antibodies. Although keeping the human ICD could favour the evaluation of cytokine production and therefore the safety of the test therapeutics, we decided to keep the mouse ICD to enable a proper interaction of CD28 with its signalling partners, allowing a physiological stimulation of CD28 in efficacy studies.Results hCD28 mice express hCD28 on T cells and the frequency of CD3 T cells is comparable in both WT and hCD28 mice. Stimulation of hCD28 mice-isolated T cells with hCD28 ligands and agonist antibodies resulted in T cell proliferation and cytokine production, suggesting that hCD28 is functional in mouse cells. MC38 uptake rate and kinetic of growth were comparable in WT and hCD28 mice, suggesting no major defect in the immune response in the hCD28 mice. Importantly, splenocytes and tumor draining lymph nodes cells isolated from tumor-bearing hCD28 mice showed higher production of IL-2 and IFN-gamma upon in vitro re-challenged with MC38 when compared to WT cells. Since the frequency of CD3 cells (Treg, CD4+ and CD8+) is comparable to WT mice, this could be explained by the expression of the amplifier CD28i isoform, which is absent in WT mice.ConclusionsThe hCD28 model described here supports the efficacy assessment of hCD28-targeting biologics, enabling PK/PD studies as hCD28 expression levels and pattern are physiological. However, after careful consideration of the CD28 biology, we decided to keep the mouse ICD, although it triggers lower pro-inflammatory cytokine production than CD28 human ICD. As such, this model is not suitable for toxicology/safety studies.ReferencePorciello N, Grazioli P, Campese AF, et al. A non-conserved amino acid variant regulates differential signalling between human and mouse CD28. Nat Commun 2018; 9:1–16.

scholarly journals Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 709
Author(s):  
Bradley M. Roberts ◽  
Emanuel F. Lopes ◽  
Stephanie J. Cragg
Keyword(s):  
Gabab Receptors ◽  
Striatal Dopamine ◽  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Short Term Plasticity ◽  
Psychomotor Disorders ◽  
Gabaa And Gabab Receptors ◽  
Uptake Transporters ◽  
Gabaergic Modulation ◽  
Da Release

Striatal dopamine (DA) release is critical for motivated actions and reinforcement learning, and is locally influenced at the level of DA axons by other striatal neurotransmitters. Here, we review a wealth of historical and more recently refined evidence indicating that DA output is inhibited by striatal γ-aminobutyric acid (GABA) acting via GABAA and GABAB receptors. We review evidence supporting the localisation of GABAA and GABAB receptors to DA axons, as well as the identity of the striatal sources of GABA that likely contribute to GABAergic modulation of DA release. We discuss emerging data outlining the mechanisms through which GABAA and GABAB receptors inhibit the amplitude as well as modulate the short-term plasticity of DA release. Furthermore, we highlight recent data showing that DA release is governed by plasma membrane GABA uptake transporters on striatal astrocytes, which determine ambient striatal GABA tone and, by extension, the tonic inhibition of DA release. Finally, we discuss how the regulation of striatal GABA-DA interactions represents an axis for dysfunction in psychomotor disorders associated with dysregulated DA signalling, including Parkinson’s disease, and could be a novel therapeutic target for drugs to modify striatal DA output.

scholarly journals Deletion of Serf2 shifts amyloid conformation in an Aβ amyloid mouse model

2021 ◽  
Author(s):  
E. Stroo ◽  
L. Janssen ◽  
O. Sin ◽  
W. Hogewerf ◽  
M. Koster ◽  
...  
Keyword(s):  
Mouse Model ◽  
Amyloid Fibrils ◽  
Mammalian Brain ◽  
Amyloid Formation ◽  
List Type ◽  
Lung Maturation ◽  
Disease Manifestation ◽  
Aβ Amyloid ◽  
Perinatal Lethality

AbstractNeurodegenerative diseases like Alzheimer, Parkinson and Huntington disease are characterized by aggregation-prone proteins that form amyloid fibrils through a nucleation process. Despite the shared β-sheet structure, recent research has shown that structurally different polymorphs exist within fibrils of the same protein. These polymorphs are associated with varying levels of toxicity and different disease phenotypes. MOAG-4 and its human orthologs SERF1 and SERF2 have previously been shown to modify the nucleation and drive amyloid formation and protein toxicity in vitro and in C. elegans. To further explore these findings, we generated a Serf2 knockout (KO) mouse model and crossed it with the APPPS1 mouse model for Aβ amyloid pathology. Full-body KO of Serf2 resulted in a developmental delay and perinatal lethality due to insufficient lung maturation. Therefore, we proceeded with a brain-specific Serf2 KO, which was found to be viable. We examined the Aβ pathology at 1 and 3 months of age, which is before and after the start of amyloid deposition. We show that SERF2 deficiency does not affect the production and overall Aβ levels. Serf2 KO-APPPS1 mice displayed an increased intracellular Aβ accumulation at 1 month and a higher number of Aβ deposits compared to APPPS1 mice with similar Aβ levels. Moreover, conformation-specific dyes and electron microscopy revealed a difference in the structure and amyloid content of these Aβ deposits. Together, our results reveal that SERF2 causes a structural shift in Aβ aggregation in a mammalian brain. These findings indicate that a single endogenous factor may contribute to amyloid polymorphisms, allowing for new insights into this phenomenon’s contribution to disease manifestation.HighlightsLoss of SERF2 slows embryonic development and causes perinatal lethalitySERF2 affects proliferation in a cell-autonomous fashionBrain-specific Serf2 knockout does not affect viability or Aβ productionBrain deletion of Serf2 shifts the amyloid conformation of Aβ

GAT-1 and Reversible GABA Transport in Bergmann Glia in Slices

2002 ◽  
Vol 88 (3) ◽  
pp. 1407-1419 ◽  
Author(s):  
L. Barakat ◽  
A. Bordey
Keyword(s):  
Gaba Receptors ◽  
Receptor Activation ◽  
Bergmann Glia ◽  
Gaba Uptake ◽  
Induced Voltage ◽  
Nipecotic Acid ◽  
Gaba Transporters ◽  
Whole Cell Patch Clamp ◽  
Inward Currents

Although glial GABA uptake and release have been studied in vitro, GABA transporters (GATs) have not been characterized in glia in slices. Whole cell patch-clamp recordings were obtained from Bergmann glia in rat cerebellar slices to characterize carrier-mediated GABA influx and efflux. GABA induced inward currents at −70 mV that could be pharmacologically separated into GABAA receptor and GAT currents. In the presence of GABAA/B/C receptor blockers, mean GABA-induced currents measured −48 pA at −70 mV, were inwardly rectifying between −70 and +50 mV, were inhibited by external Na+ removal, and were diminished by reduction of external Cl−. Nontransportable blockers of GAT-1 (SKF89976-A and NNC-711) and a transportable blocker of all the GAT subtypes (nipecotic acid) reversibly reduced GABA-induced transport currents by 68 and 100%, respectively. A blocker of BGT-1 (betaine) had no effect. SKF89976-A and NNC-711 also suppressed baseline inward currents that likely result from tonic GAT activation by background GABA. The substrate agonists, nipecotic acid and β-alanine but not betaine, induced voltage- and Na+-dependent currents. With Na+ and GABA inside the patch pipette or intracellular GABA perfusion during the recording, SKF89976-A blocked baseline outward currents that activated at −60 mV and increased with more depolarized potentials. This carrier-mediated GABA efflux induced a local accumulation of extracellular GABA detected by GABAA receptor activation on the recorded cell. Overall, these results indicate that Bergmann glia express GAT-1 that are activated by ambient GABA. In addition, GAT-1 in glia can work in reverse and release sufficient GABA to activate nearby GABA receptors.

GABA uptake regulates cortical excitability via cell type–specific tonic inhibition

2003 ◽  
Vol 6 (5) ◽  
pp. 484-490 ◽  
Author(s):  
Alexey Semyanov ◽  
Matthew C. Walker ◽  
Dimitri M. Kullmann
Keyword(s):  
Cortical Excitability ◽  
Tonic Inhibition ◽  
Gaba Uptake ◽  
Cell Type ◽  
Cell Type Specific

The MPTP mouse model: Cues on DA release and neural stem cell restorative role

2008 ◽  
Vol 14 ◽  
pp. S189-S193 ◽  
Author(s):  
Pier Andrea Serra ◽  
Stefano Pluchino ◽  
Bianca Marchetti ◽  
Maria S. Desole ◽  
Egidio Miele
Keyword(s):  
Stem Cell ◽  
Mouse Model ◽  
Neural Stem Cell ◽  
Da Release
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