Fig. 6.

Increased ATP release and contribution of CD73-mediated formation of extracellular adenosine activating A_2AR to bolster corticostriatal synaptic plasticity in the presymptomatic phase of Parkinson’s disease (PD). A The 30 mM K⁺-evoked ATP release from rat striatal nerve terminals is increased during the presymptomatic phase of PD at 7 days after administration of 6-hydroxydopamine (6-OHDA, 20 μg in each striatum) and remains upregulated throughout the protocol. B, C However, the protein levels of CD73 assessed by Western blot (B), and A_2AR density measured as the binding of the A_2A receptor antagonist ³H-SCH58261 (2 nM) (C), were not modified in striatal synapses in the presymptomatic phase and were only increased with the onset of motor symptoms at 21 days after 6-OHDA challenge. D In the presymptomatic phase of PD, corticostriatal long-term potentiation (LTP) displayed a larger amplitude, which decreased upon onset of the motor symptoms. E The recording of population spikes (PS) in rat slices showed that the CD73 inhibitor AOPCP (100 μM) decreased the high-frequency stimulation (HFS)–induced corticostriatal LTP and this effect was larger during the presymptomatic phase of PD (F) and shifted into a normalization of the depressed LTP during the symptomatic phase (G). Average alteration of the amplitude of corticostriatal LTP at different times after 6-OHDA administration and similar qualitatively effect of either blocking CD73 with AOPCP (100 μM) (H) or blocking A_2AR with SCH58261 (50 nM) (I), both of which had a larger effect on corticostriatal LTP during the presymptomatic phase of PD (J). Data are mean ± SEM of 6 rats per group; #p < 0.05 vs. control in the absence of drugs (black bars or dashed line) using a one-way ANOVA followed by Bonferroni’s post hoc test (A–D) and *p < 0.05 between indicated bars using a two-way ANOVA followed by a Newman-Keuls post hoc test (G–I)