AbstractsBiology & Animal Science

Potassium and Sodium Currents Regulating Pacemaking and Burst Firing in Substantia Nigra Dopamine Neurons

by Tilia Kimm




Institution: Harvard University
Department:
Degree: PhD
Year: 2015
Keywords: Biology, Neuroscience
Record ID: 2063246
Full text PDF: http://nrs.harvard.edu/urn-3:HUL.InstRepos:14226104


Abstract

Dopamine-releasing neurons with cell bodies in the substantia nigra pars compacta (SNc) are a primary source of dopamine in the mammalian brain. Dysfunction of dopaminergic signaling is associated with numerous psychiatric disorders, and degeneration of the SNc is one of the hallmarks of Parkinson’s disease. These neurons are autonomous pacemakers. Their spontaneous action potentials supply target areas with baseline dopaminergic tone, while synaptically-triggered bursts signal salient events. My goal was to understand the ionic currents that regulate spontaneous and burst firing in these neurons, using acutely dissociated somata from mouse SNc. Little is known about the potassium channels that participate in action potential repolarization in SNc neurons. Chapter 2 describes major complementary contributions of large conductance calcium-activated potassium (BK) channels and voltage-gated Kv2 channels. Inhibiting either type of channel individually had little effect on pacemaking because the resulting small spike broadening recruited more current through the other type and because there is a functional “reserve” of both types. In contrast, these channels regulate evoked burst firing in distinct ways: the frequency of evoked firing was increased by inhibition of Kv2 channels but decreased by inhibition of BK channels. The opposing effects on burst firing can be understood through the different channel kinetics, with BK channels activating and deactivating much faster than Kv2 channels. Sodium channels are critical components of action potential generation. Current models of SNc firing rely on sodium channel data obtained at reduced temperatures using non-physiological solutions. Chapter 3 describes characteristics of voltage-gated sodium channels in SNc neurons at 37°C using physiological ionic conditions. Based on these results, we constructed a computational model of voltage-gated sodium channels and explored how their gating helps regulate both pacemaking and burst-like firing. A variety of peptide toxins have been critical for separating currents carried by particular ion channels in central neurons. Chapter 4 describes the surprising observation that SNX-482, commonly used as a specific inhibitor of R-type Cav2.3 channels, is actually even more potent as an inhibitor of A-type potassium current in SNc neurons. Further experiments using transfected HEK-293 cells revealed that SNX-482 inhibits both Kv4.3 and Kv4.2 channels.