MPP⁺‐dependent inhibition of I_h reduces spontaneous activity and enhances EPSP summation in nigral dopamine neurons

Background and Purpose

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.

Experimental Approach

The effects of MPP⁺ on SNc DA neurons in acute midbrain slices were investigated with electrophysiology techniques.

Key Results

MPP⁺ (50 μM) was able to (i) hyperpolarize SNc DA neurons by ∼6 mV; (ii) cause an abrupt and marked (over 50%) reduction of the spontaneous activity; and (iii) inhibit the hyperpolarization‐activated inward current (I_h). MPP⁺ shifted I_h activation curve towards negative potentials by ∼11 mV both in Wistar rats and in C57/BL6 mice. Inhibition was voltage‐ and concentration‐dependent (I_max = 47%, IC₅₀ = 7.74 μM). MPP⁺ slowed I_h activation kinetics at all potentials. These effects were not dependent on (i) block of mitochondrial complex I/fall of ATP levels; (ii) activation of type 2 DA receptor; and (iii) alteration of cAMP metabolism. Finally, MPP⁺‐dependent inhibition of I_h facilitated temporal summation of evoked EPSPs in SNc DA, but not in CA1 hippocampal neurons.

Conclusion and Implications

Reduced functionality of I_h 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.

DOI: 10.1111/bph.12104

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