Brain-derived Neurotrophic Factor (BDNF) Enhances GABA Transport by Modulating the Trafficking of GABA Transporter-1 (GAT-1) from the Plasma Membrane of Rat Cortical Astrocytes

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127

115

Astrocytes play a key role in modulating synaptic transmission by controlling extracellular gamma-aminobutyric acid (GABA) levels via GAT-1 and GAT-3 GABA transporters (GATs). Using primary cultures of rat astrocytes, we show here that a further level of regulation of GABA uptake occurs via modulation of the GATs by the adenosine A 1 (A 1 R) and A 2A (A 2A R) receptors. This regulation occurs through A 1 R-A 2A R heteromers that signal via two different G proteins, G s and G i/0 , and either enhances (A 2A R) or inhibits (A 1 R) GABA uptake. These results provide novel mechanistic insight into how GPCR heteromers signal. Furthermore, we uncover a previously unknown mechanism where adenosine, in a concentrationdependent manner, acts via a heterocomplex of adenosine receptors in astrocytes to significantly contribute to neurotransmission at the tripartite (neuron-glia-neuron) synapse.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Endogenous Adenosine Tonically Modulates Gaba Uptakementioning

confidence: 99%

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A1R–A2AR heteromers coupled to Gs and Gi/0 proteins modulate GABA transport into astrocytes

Cristóvão-Ferreira

Navarro

Brugarolas

et al. 2013

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127

115

“…While A 1 receptors are widely expressed throughout the brain, A 2A receptors are most abundant in the basal ganglia, but these receptors are also present at lower density in other brain regions, namely the hippocampus. The molecular mechanisms by which the A 2A receptor controls neuronal excitability and synaptic plasticity have been extensively studied [10][11][12][13][14]. Activation of the A 2A receptor stimulates glutamate release and prevents its uptake, thus resulting in increased synaptic levels of this excitatory amino acid [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

Barros‐Barbosa

Ferreirinha

Oliveira

et al. 2016

Refractoriness to existing medications of up to 80 % of the patients with mesial temporal lobe epilepsy (MTLE) prompts for finding new antiepileptic drug targets. The adenosine A 2A receptor emerges as an interesting pharmacological target since its excitatory nature partially counteracts the dominant antiepileptic role of endogenous adenosine acting via inhibitory A 1 receptors. Gain of function of the excitatory A 2A receptor has been implicated in a significant number of brain pathologies commonly characterized by neuronal excitotoxicity. Here, we investigated changes in the expression and cellular localization of the A 2A receptor and of the adenosine-generating enzyme, ecto-5′-nucleotidase/ CD73, in the hippocampus of control individuals and MTLE human patients. Western blot analysis indicates that the A 2A receptor is more abundant in the hippocampus of MTLE patients compared to control individuals. Immunoreactivity against the A 2A receptor predominates in astrocytes staining positively for the glial fibrillary acidic protein (GFAP). No colocalization was observed between the A 2A receptor and neuronal cell markers, like synaptotagmin 1/2 (nerve terminals) and neurofilament 200 (axon fibers). Hippocampal astrogliosis observed in MTLE patients was accompanied by a proportionate increase in A 2A receptor and ecto-5′-nucleotidase/CD73 immunoreactivities. Given our data, we hypothesize that selective blockade of excessive activation of astrocytic A 2A receptors and/or inhibition of surplus adenosine formation by membrane-bound ecto-5′-nucleotidase/CD73 may reduce neuronal excitability, thus providing a novel therapeutic target for drug-refractory seizures in MTLE patients. • Ecto-5′-nucleotidase/CD73 localizes in close proximity with adenosine A 2A receptors in astrocytes of the human hippocampus. Keywords Mesial temporal lobe epilepsy (MTLE• Up-regulation of A 2A receptors and ecto-5′-nucleotidase/CD73 associates with astrogliosis of the hippocampus of MTLE patients.• Targeting astrocytic A 2A activation and/or adenosine formation via ecto-5′-nucleotidase/CD73 may control neuronal excitability.• Inhibitors of astrocytic A 2A receptors and ecto-5′-nucleotidase/CD73 may be a novel therapeutic strategy to control drug-refractory MTLE.

“…As we now show, A 2A R also contributes to BDNF-mediated inhibition of GABA release; this action of BDNF being known to result from GABA transporters modulation [16]. Considering the astrocytic component of neuronal communication, A 2A Rs also contribute BDNF-mediated modulation of GABA transport [25]. The different actions of A 2A Rs in different synapses and their ability to affect different actions of BDNF at specific sites of the tripartite synapse may allow to finely shape excitatory and inhibitory signals, thus to fine tune neuronal function.…”

Section: Discussionmentioning

confidence: 58%

Adenosine A2A receptor activation is determinant for BDNF actions upon GABA and glutamate release from rat hippocampal synaptosomes

Vaz

Lérias

Parreira

et al. 2015

Adenosine, through A 2A receptor (A 2A R) activation, can act as a metamodulator, controlling the actions of other modulators, as brain-derived neurotrophic factor (BDNF). Most of the metamodulatory actions of adenosine in the hippocampus have been evaluated in excitatory synapses. However, adenosine and BDNF can also influence GABAergic transmission. We thus evaluated the role of A 2A R on the modulatory effect of BDNF upon glutamate and GABA release from isolated hippocampal nerve terminals (synaptosomes). BDNF (30 ng/ml) enhanced K + -evoked [ 3 H]glutamate release and inhibited the K + -evoked [ 3 H]GABA release from synaptosomes. The effect of BDNF on both glutamate and GABA release requires tonic activation of adenosine A 2A R since for both neurotransmitters, the BDNF action was blocked by the A 2A R antagonist SCH 58261 (50 nM). In the presence of the A 2A R agonist, CGS21680 (30 nM), the effect of BDNF on either glutamate or GABA release was, however, not potentiated. It is concluded that both the inhibitory actions of BDNF on GABA release as well as the facilitatory action of the neurotrophin on glutamate release are dependent on the activation of adenosine A 2A R by endogenous adenosine. However, these actions could not be further enhanced by exogenous activation of A 2A R.