Dual function of Zn²⁺ on the intrinsic excitability of dopaminergic neurons in rat substantia nigra

Despite the presence of Zn²⁺ in high levels in Parkinson brain, it is not yet clearly answered whether and how Zn²⁺ alters the electrical activity of neurons in substantia nigra (SN). Here we show that Zn²⁺ alters the intrinsic activity of nigral dopamine neurons in dual ways, that is, excitation or inhibition, by modulating the gating properties of a transient A-type K⁺ (K_A) channel. Depending on the holding potential, Zn²⁺ could reduce or enhance a transient outward K⁺ current (I_A) in nigral dopamine neurons. Zn²⁺ slowed the kinetics of both I_A activation and inactivation with the rate of activation much more reduced than that of inactivation. Zn²⁺ also increased the rate of release from I_A inactivation. Both activation and inactivation I_A curves were shifted by Zn²⁺ towards positive potentials, but the positive shift of the inactivation curve was much greater than that of the activation curve. We propose that all these effects of Zn²⁺ on K_A channel gating properties underlie the dual mode of Zn²⁺ action on I_A, that is, attenuation or potentiation depending on membrane potential. As a result, Zn²⁺ increased a bursting activity of a nigral dopamine neuron elicited by anodal break excitation presumably through I_A reduction at a hyperpolarizing state, whereas Zn²⁺ decreased its tonic activity at either resting or depolarizing states where I_A was increased. This was further supported by the observations that 4-aminopyridine (4-AP), a well-known K_A channel blocker, strengthened or counteracted the effect of Zn²⁺ on the intrinsic excitability of nigral dopamine neurons.