Une nouvelle hypothèse sur le mécanisme de pacemaking dans les neurones dopaminergiques de la substance noire compacte

Substantia Nigra pars compacta dopamine neurons are integrated in the nigrostriatal pathways of the basal ganglia. They release dopamine in the striatum to modulate the activity of the different nuclei from the basal ganglia. Thus, those neurons are involved in motor control, as well as exploration and motivation behaviors. Dopamine release disruption, due to neurodegeneration, leads to various motor impairment (Parkinson Disease) and behavioral diseases. Dopamine release is controlled by the electrical activity of dopamine neurons. The firing pattern of these neurons is controlled by synaptic activity in vivo. They can present a regular firing called “pacemaking”, an irregular firing or a bursting firing. Only the pacemaking activity remains in vitro. This regular firing is therefore sustained and controlled by intrinsic conductances. However, the exact mechanism underlying Substantia Nigra pars compacta dopamine neurons pacemaking activity remains unclear. In fact, blocking one or few conductances only affects the firing frequency but it does not fully inhibit the spontaneous activity. In order to sustain such activity, it has been showed that a small inward current is activated during the slow depolarization phase between two action potentials in ventral tegmental area dopamine neurons (Khaliq and Bean, 2008). Given the similar properties within midbrain dopamine neurons being heterogenous, it is not excluded that their pacemaking is mediated by one and same conductance.
We investigated several potential candidates, including the unconventional conductance mediated by ω pores. We used the only known blockers of such pores, 1-(2,4-xylyl)guanidine (XG), in order to verify our hypothesis. We observed that this compound is able to selectively inhibit midbrain dopamine neurons pacemaking activity by blocking one target, without affecting either the burst activity nor the ion channels underlying action potentials. We also observed that the effect of XG still persists even when the pacemaking main modulators are being blocked. These results demonstrate that the XG-sensitive conductance is crucial to sustain the spontaneous activity in midbrain dopamine neurons. We next investigated the presence of ω pores but we did not observe evidence in favor of this hypothesis. However, we managed to isolate a XG-sensitive current occurring during the interspike interval corresponding the pacemaker current described by Khaliq and Bean. We characterized this current and found that it is sustained by Na+ and Cl-. Finally, we investigated whether this current was sustained by the dopamine transporter because it displays similar properties. We used transgenic mice lacking the dopamine transporter in dopamine neurons. We found that the absence of the transporter did not affect either the firing frequency nor XG effect on those neurons.
To conclude, even though we did not manage to identify the molecular target of XG, we emphasized a new conductance crucial to sustain pacemaking activity in midbrain dopamine neurons.