Dataset Information

Increased ATP Release and Higher Impact of Adenosine A_2A Receptors on Corticostriatal Plasticity in a Rat Model of Presymptomatic Parkinson's Disease.

ABSTRACT: Extracellular ATP can be a danger signal, but its role in striatal circuits afflicted in Parkinson's disease (PD) is unclear and was now investigated. ATP was particularly released at high stimulation intensities from purified striatal nerve terminals of mice, which were endowed with different ATP-P2 receptors (P2R), although P2R antagonists did not alter corticostriatal transmission or plasticity. Instead, ATP was extracellularly catabolized into adenosine through CD73 to activate adenosine A_2A receptors (A_2AR) modulating corticostriatal long-term potentiation (LTP) in mice. In the presymptomatic phase of a 6-hydroxydopamine rat model of PD, ATP release from striatal nerve terminals was increased and was responsible for a greater impact of CD73 and A_2AR on corticostriatal LTP. These observations identify increased ATP release and ATP-derived formation of extracellular adenosine bolstering A_2AR activation as a key pathway responsible for abnormal synaptic plasticity in circuits involved in the onset of PD motor symptoms. The translation of these findings to humans prompts extending the use of A_2AR antagonists from only co-adjuvants of motor control in Parkinsonian patients to neuroprotective drugs delaying the onset of motor symptoms.

SUBMITTER: Goncalves FQ

PROVIDER: S-EPMC9899190 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Increased ATP Release and Higher Impact of Adenosine A<sub>2A</sub> Receptors on Corticostriatal Plasticity in a Rat Model of Presymptomatic Parkinson's Disease.

Gonçalves Francisco Q FQ Matheus Filipe C FC Silva Henrique B HB Real Joana I JI Rial Daniel D Rodrigues Ricardo J RJ Oses Jean-Pierre JP Silva António C AC Gonçalves Nélio N Prediger Rui D RD Tomé Ângelo R ÂR Cunha Rodrigo A RA

Molecular neurobiology 20221222 3

Extracellular ATP can be a danger signal, but its role in striatal circuits afflicted in Parkinson's disease (PD) is unclear and was now investigated. ATP was particularly released at high stimulation intensities from purified striatal nerve terminals of mice, which were endowed with different ATP-P2 receptors (P2R), although P2R antagonists did not alter corticostriatal transmission or plasticity. Instead, ATP was extracellularly catabolized into adenosine through CD73 to activate adenosine A<s ...[more]

PMID: 36547848

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Project description:Background and purposeLrp4 (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.MethodsThe 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.ResultsLrp4, 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.ConclusionsThe 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.

Dataset Information

Increased ATP Release and Higher Impact of Adenosine A_2A Receptors on Corticostriatal Plasticity in a Rat Model of Presymptomatic Parkinson's Disease.

Publications

Increased ATP Release and Higher Impact of Adenosine A<sub>2A</sub> Receptors on Corticostriatal Plasticity in a Rat Model of Presymptomatic Parkinson's Disease.

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Dataset Information

Increased ATP Release and Higher Impact of Adenosine A2A Receptors on Corticostriatal Plasticity in a Rat Model of Presymptomatic Parkinson's Disease.

Publications

Increased ATP Release and Higher Impact of Adenosine A<sub>2A</sub> Receptors on Corticostriatal Plasticity in a Rat Model of Presymptomatic Parkinson's Disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Increased ATP Release and Higher Impact of Adenosine A_2A Receptors on Corticostriatal Plasticity in a Rat Model of Presymptomatic Parkinson's Disease.