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Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity.

ABSTRACT: Adenosine is a potent anticonvulsant acting on excitatory synapses through A1 receptors. Cellular release of ATP, and its subsequent extracellular enzymatic degradation to adenosine, could provide a powerful mechanism for astrocytes to control the activity of neural networks during high-intensity activity. Despite adenosine's importance, the cellular source of adenosine remains unclear. We report here that multiple enzymes degrade extracellular ATP in brain tissue, whereas only Nt5e degrades AMP to adenosine. However, endogenous A1 receptor activation during cortical seizures in vivo or heterosynaptic depression in situ is independent of Nt5e activity, and activation of astrocytic ATP release via Ca(2+) photolysis does not trigger synaptic depression. In contrast, selective activation of postsynaptic CA1 neurons leads to release of adenosine and synaptic depression. This study shows that adenosine-mediated synaptic depression is not a consequence of astrocytic ATP release, but is instead an autonomic feedback mechanism that suppresses excitatory transmission during prolonged activity.

SUBMITTER: Lovatt D

PROVIDER: S-EPMC3341061 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity.

Lovatt Ditte D Xu Qiwu Q Liu Wei W Takano Takahiro T Smith Nathan A NA Schnermann Jurgen J Tieu Kim K Nedergaard Maiken M

Proceedings of the National Academy of Sciences of the United States of America 20120315 16

Adenosine is a potent anticonvulsant acting on excitatory synapses through A1 receptors. Cellular release of ATP, and its subsequent extracellular enzymatic degradation to adenosine, could provide a powerful mechanism for astrocytes to control the activity of neural networks during high-intensity activity. Despite adenosine's importance, the cellular source of adenosine remains unclear. We report here that multiple enzymes degrade extracellular ATP in brain tissue, whereas only Nt5e degrades AMP ...[more]

PMID: 22421436

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Project description:Background and purposeIschemic stroke significantly perturbs neuronal homeostasis leading to a cascade of pathologic events causing brain damage. In this study, we assessed acute stroke outcome after chemogenetic inhibition of forebrain excitatory neuronal activity.MethodsWe generated hM4Di-TG transgenic mice expressing the inhibitory hM4Di, a Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic receptor, in forebrain excitatory neurons. Clozapine-N-oxide (CNO) was used to activate hM4Di DREADD. Ischemic stroke was induced by transient occlusion of the middle cerebral artery. Neurologic function and infarct volumes were evaluated. Excitatory neuronal suppression in the hM4Di-TG mouse forebrain was assessed electrophysiologically in vitro and in vivo, based on evoked synaptic responses, and in vivo based on occurrence of potassium-induced cortical spreading depolarizations.ResultsDetailed characterization of hM4Di-TG mice confirmed that evoked synaptic responses in both in vitro hippocampal slices and in vivo motor cortex were significantly reduced after CNO-mediated activation of the inhibitory hM4Di DREADD. Further, CNO treatment had no obvious effects on physiology and motor function in either control or hM4Di-TG mice. Importantly, hM4Di-TG mice treated with CNO at either 10 min before ischemia or 30 min after reperfusion exhibited significantly improved neurologic function and smaller infarct volumes compared to CNO-treated control mice. Mechanistically, we showed that potassium-induced cortical spreading depression episodes were inhibited, including frequency and duration of DC shift, in CNO-treated hM4Di-TG mice.ConclusionsOur data demonstrate that acute inhibition of a subset of excitatory neurons after ischemic stroke can prevent brain injury and improve functional outcome. This study, together with the previous work in optogenetic neuronal modulation during the chronic phase of stroke, supports the notion that targeting neuronal activity is a promising strategy in stroke therapy.

Project description:BACKGROUND AND PURPOSE:Lrp4 (low-density lipoprotein receptor-related protein 4) is predominantly expressed in astrocytes, where it regulates glutamatergic neurotransmission by suppressing ATP release. Here, we investigated Lrp4's function in ischemia/stroke-induced brain injury response, which includes glutamate-induced neuronal death and reactive astrogliosis. METHODS:The brain-specific Lrp4 conditional knockout mice (Lrp4GFAP-Cre), astrocytic-specific Lrp4 conditional knockout mice (Lrp4GFAP-creER), and their control mice (Lrp4f/f) were subjected to photothrombotic ischemia and the transient middle cerebral artery occlusion. After ischemia/stroke, mice or their brain samples were subjected to behavior tests, brain histology, immunofluorescence staining, Western blot, and quantitative real-time polymerase chain reaction. In addition, primary astrocytes and neurons were cocultured with or without oxygen and glucose deprivation and in the presence or absence of the antagonist for adenosine-A2AR (adenosine A2A receptor) or ATP-P2X7R (P2X purinoceptor 7) signaling. Gliotransmitters, such as glutamate, d-serine, ATP, and adenosine, in the condition medium of cultured astrocytes were also measured. RESULTS:Lrp4, largely expressed in astrocytes, was increased in response to ischemia/stroke. Both Lrp4GFAP-Cre and Lrp4GFAP-creER mice showed less brain injury, including reduced neuronal death, and impaired reactive astrogliosis. Mechanistically, Lrp4 conditional knockout in astrocytes increased ATP release and the production of ATP derivative, adenosine, which were further elevated by oxygen and glucose deprivation. Pharmacological inhibition of ATP-P2X7R or adenosine-A2AR signaling diminished Lrp4GFAP-creER's protective effect. CONCLUSIONS:The astrocytic Lrp4 plays an important role in ischemic brain injury response. Lrp4 deficiency in astrocytes seems to be protective in response to ischemic brain injury, likely because of the increased ATP release and adenosine-A2AR signaling.

Project description:Strategies are needed to reverse the immune cell hyporesponsiveness and prevent bacterial overgrowth associated with high mortality rates in septic patients. Adenosine signaling may be mediating immunosuppressive signals within the inflammatory microenvironment that are safeguarding bacteria by rendering immune cells hyporesponsive. We examined A2A adenosine receptor (A2AR)-mediated immune responses in a chronic model of cecal ligation and puncture (CLP)-induced sepsis using both wild-type (WT) and A2AR knockout (KO) mice. In this model, chronic bacterial peritonitis was established that results in the first death on day 4. A2A adenosine receptors promoted bacterial overgrowth that was associated with a high 28-day sepsis mortality (WT 87% vs. A2AR KO 13%; P < 0.0001). Chronic bacteremia persisted in both WT and A2AR KO mice over the 28-day study period. Bacteremia was significantly decreased in A2AR KO mice 2 days after antibiotic therapy cessation (day 6 after CLP; P < 0.005). Local and disseminated bacteria levels were compared at the end of the 28-day study period or from moribund mice. A2A adenosine receptor deficiency dramatically decreased peritoneal (P < 0.05), splenic (P < 0.05), and blood (P < 0.01) bacterial levels. A2A adenosine receptor deficiency caused an early reduction in inflammatory mediators IL-6, macrophage inflammatory protein 2, TNF-srI, and TNF-srII (P < 0.05), but not in TNF-?, IL-1?, IL-10, or monocyte chemotactic protein 1 within 24 h after CLP. In response to an intravenous lipopolysaccharide (day 5 after CLP) challenge, A2AR KO mice showed enhanced secretion of TNF-? (2 h), IFN-?, IL-6, monocyte chemotactic protein 1, IL-10, and macrophage inflammatory protein 2 (9 h) (P < 0.05), suggesting that A2ARs attenuate inflammatory responses to repeat infectious insults. These data demonstrate that A2AR blockade may be an effective immunotherapy treatment to prevent bacterial overgrowth and reduce mortality secondary to immunosuppression in septic patients.

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Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity.

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Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity.

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