Phosphodiesterase 10A controls D1-mediated facilitation of GABA release from striato-nigral projections under normal and dopamine-depleted conditions

• Importance of pre-synaptic cAMP signaling/degradation to control of SNpr activity.
• Involvement of PDE10A in D1R-mediated GABA release in the SNpr.
• D1Rs require concomitant inhibition of PDE10A in order to facilitate GABA release.
• In the striatum of DA-depleted mice PDE10A levels are reduced.

In the present study, we found that PDE10A inhibitor papaverine, alone or in combination with the D1 receptor agonist SKF38393, did not change spontaneous IPSCs (sIPSCs) frequency or amplitude in the substantia nigra pars reticulata (SNpr). An increase in frequency, but not in amplitude, of sIPSCs was only observed when SKF38393 and PDE10A inhibitors were associated to perfusion with higher extracellular K+. On the other hand, the amplitude of evoked IPSCs (eIPSCs) of the striato-nigral projection to SNpr, was increased in response to co-administration of SKF38393 and papaverine in normal extracellular potassium. Of note, both an increase in sIPSCs frequency and eIPSC amplitude could be obtained either by a robust stimulation of adenylyl cyclase (AC) with forskolin (10 μM) or by a lower dose of forskolin (1 μM) associated to PDE inhibition. We next investigated the effects produced by dopamine (DA) depletion in the striatum. Under this condition, SKF38393 alone increased either sIPSCs frequency and eIPSC amplitude. In addition, in the striatum of DA-depleted mice we found reduced PDE10A levels and higher cAMP-dependent phosphorylation in response to D1 receptor stimulation. In accordance with these biochemical data, perfusion with papaverine had no effect on the SKF38393-induced changes of IPSCs in slices of DA-depleted mice. These findings reveal a dynamic interplay between PDE10A activity, level of neuronal network depolarization and degree of dopaminergic tone in the ability of D1 receptors to facilitate the GABAergic transmission to SNpr neurons from the direct nigro-striatal pathway.This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’.