THE DUAL ROLE OF THE P2Y1 RECEPTOR IN MOTOR CONTROL IN PHYSIOLOGICAL AND 6-OHDA HEMI-PARKINSONIAN CONDITIONS

The neurodegeneration of dopaminergic neurons (DNs) in the substantia nigra pars compacta (SNpc) involves exacerbated inflammation with astrocyte involvement. The P2Y1 receptor (P2Y1R) is highly expressed in the basal ganglia (BG) structures and astrocytes, regulating astrocyte activity and proliferation. Despite its recognized role in brain pathologies, the contribution of P2Y1R to BG function and Parkinson’s disease remains poorly investigated. Therefore, we investigated whether the P2Y1R modulates BG circuitry and DN degeneration. Using whole-cell patch clamp, we recorded the activity of GABAergic medium spiny neurons (MSNs) in the striatum (STR) and DNs in the SNpc in D2-GFP mice. DN degeneration was induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA). Under physiological conditions, the P2Y1R was detected in DNs and astrocytes in SNpc and STR. Pharmacological P2Y1R activation MRS2365 reduced the excitability of SNpc DNs and STR D2-MSN, without affecting D1-MSN. Seven days after 6-OHDA, P2Y1R expression was increased in both STR and SNpc and, in brain slices, DNs and MSNs were hyperexcitable. P2Y1R inhibition (MRS2179) restored the exacerbated spontaneous activity of surviving DNs and the evoked activity of D2-SPNs, while reducing in D1-SPNs. Conversely, MRS2365 exacerbated evoked activity of remaining DNs, although it reduced the spontaneous activity. Notably, in vivo experiments revealed contrasting outcomes: intranasal administration of MRS2365 worsened motor impairment and DN degeneration, whereas intracerebroventricular infusion of either MRS2365 or MRS2179 altered motor performance without affecting neuronal loss. These findings demonstrate that P2Y1R is functionally expressed in BG and displays divergent functional roles in physiological and hemi-parkinsonian states.