4.6 Article

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

Journal

MOLECULAR NEUROBIOLOGY
Volume 60, Issue 3, Pages 1659-1674

Publisher

SPRINGER
DOI: 10.1007/s12035-022-03162-1

Keywords

Adenosine; Ecto-5 '-nucleotidase; A(2A) receptors; Parkinson's disease; ATP

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The increased release of ATP and the subsequent formation of extracellular adenosine, which activates A(2A)R, play a key role in the abnormal synaptic plasticity associated with the onset of motor symptoms in Parkinson's disease.
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(2A)R) 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(2A)R on corticostriatal LTP. These observations identify increased ATP release and ATP-derived formation of extracellular adenosine bolstering A(2A)R 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(2A)R antagonists from only co-adjuvants of motor control in Parkinsonian patients to neuroprotective drugs delaying the onset of motor symptoms.

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