Recent work has established hydrogen peroxide as a signaling molecule in basal ganglia nuclei including the striatum and the substantia nigra pars compacta. The current proposal seeks to examine the functions of hydrogen peroxide as a signaling molecule in the substantia nigra pars reticulata (SNr) which has not been examined previously. In vitro visualized whole cell current clamp recordings of nigral GABAergic neurons will be used to record their activity while applying exogenous hydrogen peroxide, and more importantly, while enhancing endogenous hydrogen peroxide levels by inhibiting peroxidase enzymes, which will be verified using the fluorescent hydrogen peroxide-sensitive indicator, dichlorodihydrofluorescein (DCF). The channels underlying hydrogen peroxide's effects will be uncovered by combining manipulations of hydrogen peroxide levels with pharmacological blockers of metabolically activated nonselective cation channels (namely TRPM) and ATP-sensitive potassium channels (K-ATP), both of which have been shown by the Rice group to be important targets for hydrogen peroxide in other basal ganglia nuclei. The activation of TRPM and K- ATP channels would be expected to increase and decrease the excitability of SNr GABAergic neurons respectively. In other experiments, fast-scan cyclic voltammetry will be used to determine whether hydrogen peroxide-induced excitation of SNr GABAergic neurons contributes to the previously observed suppression of somatodendritic dopamine release in the substantia nigra caused by hydrogen peroxide. The effects of hydrogen peroxide on NMDA-induced burst firing will also be studied, providing an additional functional consequence for hydrogen peroxide signaling in the SNr. The GABAergic output neurons of the SNr convey the output of the entire basal ganglia network to target nuclei in the thalamus and superior colliculus. In addition to mediating the physiological role of the basal ganglia in the control of normal movement, it is altered activity of SNr output neurons which also seems to underlie many of the pathophysiological features of Parkinson's disease and other movement disorders. Elucidating key factors that modulate the excitability of nigral GABAergic output neurons is an important prerequisite to understanding the physiological properties of these neurons under both normal and pathological conditions and ultimately lead to discovery of novel therapeutic targets for movement disorders. Specifically, hydrogen peroxide might contribute to increases in the excitability of SNr neurons in Parkinson's disease, the potential mechanisms and consequences of which will be studied here.
|Lee, Christian R; Patel, Jyoti C; O'Neill, Brian et al. (2015) Inhibitory and excitatory neuromodulation by hydrogen peroxide: translating energetics to information. J Physiol 593:3431-46|
|Lee, Christian R; Machold, Robert P; Witkovsky, Paul et al. (2013) TRPM2 channels are required for NMDA-induced burst firing and contribute to H(2)O(2)-dependent modulation in substantia nigra pars reticulata GABAergic neurons. J Neurosci 33:1157-68|
|Zhou, F-M; Lee, C R (2011) Intrinsic and integrative properties of substantia nigra pars reticulata neurons. Neuroscience 198:69-94|
|Rice, Margaret E (2011) H2O2: a dynamic neuromodulator. Neuroscientist 17:389-406|
|Lee, Christian R; Witkovsky, Paul; Rice, Margaret E (2011) Regulation of Substantia Nigra Pars Reticulata GABAergic Neuron Activity by H?O? via Flufenamic Acid-Sensitive Channels and KATPChannels. Front Syst Neurosci 5:14|