Regulation of substantia nigra pars reticulata GABAergic neuron activity by H 2O 2 via fufenamic acid-sensitive channels and K ATP channels

Abstract

Substantia nigra pars reticulata (SNr) GABAergic neurons are key output neurons of the basal ganglia. Given the role of these neurons in motor control, it is important to understand factors that regulate their firing rate and pattern. One potential regulator is hydrogen peroxide (H 2O 2), a reactive oxygen species that is increasingly recognized as a neuromodulator. We used whole-cell current clamp recordings of SNr GABAergic neurons in guinea-pig midbrain slices to determine how H 2O 2 affects the activity of these neurons and to explore the classes of ion channels underlying those effects. Elevation of H 2O 2 levels caused an increase in the spontaneous firing rate of SNr GABAergic neurons, whether by application of exogenous H 2O 2 or amplification of endogenous H 2O 2 through inhibition of glutathione peroxidase with mercaptosuccinate. This effect was reversed by flufenamic acid (FFA), implicating transient receptor potential (TRP) channels. Conversely, depletion of endogenous H 2O 2 by catalase, a peroxidase enzyme, decreased spontaneous firing rate and firing precision of SNr neurons, demonstrating tonic control of firing rate by H 2O 2. Elevation of H 2O 2 in the presence of FFA revealed an inhibition of tonic firing that was prevented by blockade of ATP-sensitive K + (K ATP) channels with glibenclamide. In contrast to guinea-pig SNr neurons, the dominant effect of H 2O 2 elevation in mouse SNr GABAergic neurons was hyperpolarization, indicating a species difference in H 2O 2-dependent regulation. Thus, H 2O 2 is an endogenous modulator of SNr GABAergic neurons, acting primarily through presumed TRP channels in guinea-pig SNr, with additional modulation via K ATP channels to regulate SNr output. © 2011 Lee, Witkovsky and Rice.