Acute actions of parkinsonizing toxin MPP+ reveal new functions for the hyperpolarization-activated current in the physiology and pathology of midbrain dopaminergic neurons

1-Methyl-4-phenylpyridinium (MPP(+) ), a potent parkinsonizing agent in primates and rodents, is a blocker of mitochondrial complex I, therefore MPP(+) -induced parkinsonism is believed to depend largely on mitochondrial impairment. However, it has recently been proposed that other mechanisms may participate in MPP(+) -induced toxicity. We tackled this issue by probing the effects of an acute application of MPP(+) on substantia nigra pars compacta (SNc) dopamine (DA) neurons. On these premises, we decided to study the effects of MPP(+) on SNc DA neurons in acute midbrain slices with electrophysiology techniques. Results MPP(+) (50 μM) was able to hyperpolarize SNc DA neurons by ∼6 mV; cause an abrupt and marked (over 50%) reduction of the spontaneous activity; and inhibit the hyperpolarization-activated inward current (Ih ). MPP(+) shifted Ih activation curve towards negative potentials by ∼11 mV both in Wistar rats and in C57/BL6 mice. Inhibition was voltage- and concentration-dependent (Imax = 47%, IC50 = 7.74 μM). MPP(+) slowed Ih activation kinetics at all potentials. These effects were not dependent of block of mitochondrial complex I/fall of ATP levels; activation of type 2 DA receptor; and alteration of cAMP metabolism. Finally, MPP(+) -dependent inhibition of Ih facilitated temporal summation of evoked EPSPs in SNc DA, but not in CA1 hippocampal neurons. Conclusions Reduced functionality of Ih in SNc DA neurons, via increased responsiveness towards synaptic excitation, might play a role in MPP(+) -induced parkinsonism and, possibly, in the pathogenesis of human Parkinson's.