Determinants of the pace, precision, and pattern of firing of subthalamic nucleus neurons in vitro: Contributions of small-conductance calcium -activated potassium channels and coupled voltage -gated calcium channels, and mechanisms of gamma-aminobutyric

The neurons of the subthalamic nucleus (STN) are positioned to influence the output of the basal ganglia. The dynamics of action potential generation in STN neurons are dictated by the complement of ion channels that underlie autonomous activity and the manner in which synaptic input is integrated.;The gamma-aminobutyric acid (GABAergic) GP provides a major inhibitory afferent to the STN. A parasagittal slice preparation was developed to investigate the mechanisms underlying the GABAergic inhibition of STN neurons. Voltage-clamp recordings revealed spontaneous action potential-dependent GABAA currents. Postsynaptic GABAA receptors were not tonically activated and GABA transporter blockade had no impact on recorded miniature synaptic currents. Perforated patch current-clamp recordings revealed barrages of spontaneous inhibitory postsynaptic potentials (IPSPs) that caused STN neurons to discharge in an irregular manner. Indeed, GABAA antagonists significantly increased the pace and precision of STN activity. Electrical stimulation of the GP evoked GABAA IPSPs in STN neurons, confirming that the pallidal projection was intact. Stimulation also evoked GABAB IPSPs in a limited number of cases. While GABAB antagonists had no effect under baseline conditions, they significantly increased the firing rate of STN neurons under conditions of elevated GABA release.;Taken together, these data elucidate the contribution of specific intrinsic and extrinsic factors that control the excitability of STN neurons.;To determine the contribution of small-conductance calcium-activated potassium (SKCa) channels, STN neurons were recorded in vitro using the perforated patch-clamp technique. Voltage-clamp recordings revealed that single-spike afterhyperpolarization was blocked by the SK Ca antagonist, apamin, and enhanced by the agonist, 1-ethyl-2-benzimidazolinone. Current-clamp recordings demonstrated that apamin-sensitive current was critical for precise single-spike firing, contributed to the dynamic response to depolarizing input, and shaped rebound burst responses. Blockade of SKCa channels promoted the transition from autonomous single-spike activity to burst firing. Coupling of specific voltage-gated calcium (CaV) channels and the activation of apamin-sensitive current was also assessed in individual STN neurons. o-conotoxin GVIA application produced apamin-like effects, suggesting calcium entry through CaV2.2 channels contributed to the activation of SKCa channels. Nifedipine-sensitive CaV 1.2--1.3 channels were not strongly coupled to SKCa channels, and therefore supported high-frequency driven activity and long-duration rebound burst firing.