Increased ATP Release and Higher Impact of Adenosine A2A 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 A2A receptors (A2AR) 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 A2AR on corticostriatal LTP. These observations identify increased ATP release and ATP-derived formation of extracellular adenosine bolstering A2AR 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 A2AR antagonists from only co-adjuvants of motor control in Parkinsonian patients to neuroprotective drugs delaying the onset of motor symptoms.

Increased Synaptic ATP Release and CD73-Mediated Formation of Extracellular Adenosine in the Control of Behavioral and Electrophysiological Modifications Caused by Chronic Stress

“…Thus, the P 2 R-mediated antidepressant effect of exogenously added ATP − is unlikely to be exerted directly within synapses but instead likely results from extra-synaptic actions, eventually associated with overactivation of A 1 R . This is further supported by our previous observations that although different P 2 Rs are located in hippocampal and striatal synapses, P 2 R antagonists have a limited impact on synaptic plasticity in the hippocampus or in the striatum hinting at a more relevant role of indirect and extra-synaptic rather than synaptic P 2 R to control information processing in cortical circuits. − …”

“…To selectively study the release of ATP from nerve terminals, we purified synaptosomes since the K + -induced release of ATP from synaptosomes reflects a vesicular release of ATP. ,, We now report that the depolarization of rat hippocampal synaptosomes, by raising the extracellular concentration of K + to 30 mM, triggered a rapid increase of extracellular ATP measured by its luminometric detection using the luciferin-luciferase assay (Figure A, black line). The average K + -evoked ATP release from hippocampal synaptosomes of control animals was 21.6 ± 1.6 pmol/mg protein ( n = 6), a value similar to that reported previously by others using synaptosomes purified from different brain areas. , As shown in the representative traces of Figure A, the K + -induced ATP release was larger in hippocampal synaptosomes collected from rats subject to repeated restraint stress, reaching a value of 39.5 ± 3.1 pmol/mg protein ( n = 6, t = 5.173, p = 0.001 vs control).…”

“…Thus, in view of the well-established role of synaptic A 2A R overfunction to control aberrant plasticity associated with mood alterations, we now explored how the release of ATP from synapses was selectively affected in conditions of chronic stress and if an increased ATP-derived adenosine formation was also critical to sustain A 2A R overfunction in excitatory synapses, as was previously observed in animal models of different brain diseases such as Alzheimer’s disease, Parkinson’s disease, , epilepsy, fear memory, or fatigue. , …”

“…Adenosine mainly acts through inhibitory adenosine A 1 receptors and facilitatory adenosine A 2A receptors (A 2A R) to assist encoding salience of information in neuronal circuits . This parallel activation of A 1 R and A 2A R is ensured by different sources of adenosine: activation of A 1 R results from ATP/adenosine released from astrocytes, − from microglia , or from postsynaptic compartments of neurons through bidirectional nucleoside transporters, whereas synaptically released ATP-derived formation of extracellular adenosine through ecto-nucleotidases is selectively associated with the activation of adenosine A 2A R controlling synaptic plasticity processes. − Understanding the dynamics of the adenosine modulation system is relevant to control neurodegeneration in accordance with the view that chronic brain diseases begin by a dysfunction and damage of synapses (reviewed in refs and ), mainly of excitatory synapses. , …”

“…This implies an overfunction of purinergic A 2A R and P 2X7 R, which apparently contrasts with the proposed antidepressant role of ATP based on the reported decreased ATP levels associated with depression. − This is particularly surprising since ATP is a danger signal in the brain (reviewed in ref ), and there is an increased ATP release in different brain diseases, ,,, in particular in synapses that are particularly affected at the onset of depressive conditions (reviewed in ref ). Notably, the observed decrease of ATP release in depressive-like conditions was proposed to originate from astrocytes, ,,, which release ATP through lysosome exocytosis, through transmembrane Calhm2 channel proteins, through pannexin-1 channel, and through connexin-43, whereas the release of ATP from nerve terminals is mostly vesicular in nature. − Furthermore, ATP release from astrocytes is designed to entrain a volume-like heterosynaptic depression , and is expected to overshadow the vesicular release of ATP from nerve terminals, which only represent ∼1% of gray matter volume, designed to act within the synapse to bolster synaptic plasticity through A 2A R activation after its local extracellular catabolism by ecto-nucleotidases. − …”