BackgroundStriatal fast-spiking interneurons (FSI) are a subset of GABAergic cells that express calcium-binding protein parvalbumin (PV). They provide feed-forward inhibition to striatal projection neurons (SPNs), receive cortical, thalamic and dopaminergic inputs and are coupled together by electrical and chemical synapses, being important components of the striatal circuitry. It is known that dopamine (DA) depolarizes FSI via D1-class DA receptors, but no studies about the ionic mechanism of this action have been reported. Here we ask about the ion channels that are the effectors of DA actions. This work studies their Ca2+ currents.ResultsWhole-cell recordings in acutely dissociated and identified FSI from PV-Cre transgenic mice were used to show that FSI express an array of voltage gated Ca2+ channel classes: CaV1, CaV2.1, CaV2.2, CaV2.3 and CaV3. However, CaV1 Ca2+ channel carries most of the whole-cell Ca2+ current in FSI. Activation of D1-like class of DA receptors by the D1-receptor selective agonist SKF-81297 (SKF) enhances whole-cell Ca2+ currents through CaV1 channels modulation. A previous block of CaV1 channels with nicardipine occludes the action of the DA-agonist, suggesting that no other Ca2+ channel is modulated by D1-receptor activation. Bath application of SKF in brain slices increases the firing rate and activity of FSI as measured with both whole-cell and Ca2+ imaging recordings. These actions are reduced by nicardipine.ConclusionsThe present work discloses one final effector of DA modulation in FSI. We conclude that the facilitatory action of DA in FSI is in part due to CaV1 Ca2+ channels positive modulation.

Adenosine A1 and A2A receptors are expressed in striatal projection neurons (SPNs). A1 receptors are located in direct (dSPN) and indirect SPNs (iSNP). A2A receptors are only present in iSPNs. Dopamine D2 receptors are also expressed in iSPNs and interactions between D2 and A2A receptors have received attention. iSPNs activity increases during parkinsonism (PD) and A2A receptors may be responsible by enhancing Ca2+ currents (iCa2+). Therefore, A2A receptors blockade is a therapeutic approach. We asked whether A2A receptors need the interaction with D2 receptors (D2R) to exert their actions. By using isolated and identified iSPNs to avoid indirect influences, we show that D2R action habilitates A2A receptors (A2AR) modulation. iCa2+ through voltage gated Ca2+ channels (CaV) was used as a signal to observe this interaction. Voltage-clamp recordings in acutely dissociated iSPNs, current-clamp recordings in slices and calcium imaging in transgenic A2A-Cre mice, showed that D2R reduction in iCa2+ endows A2AR to restore iCa2+ on iSPNs showing an antagonistic interaction between D2 and A2A receptors. A2A receptors were blocked by the antagonist istradefylline, however, this blockade differed in control and dopamine-depleted iSPNs: istradefylline reduced D2R modulation in parkinsonian animals as compared to controls. Calcium imaging recordings show that istradefylline occludes D2R actions in the parkinsonian circuitry and this effect depends on the order of drugs application. Thus, while D2 activation enables A2A receptors action, blockade of A2AR induces a reduction in the action of D2 agonists, confirming a complex interaction. Summary Statement A2A receptor required previous D2 receptor activation to modulate Ca2+ currents. Istradefylline decreases pramipexole modulation on Ca2+ currents. Istradefylline reduces A2A + neurons activity in striatial microcircuit, but pramipexole failed to further reduce neuronal activity.