Group I mGluRs modulate calcium currents in rat GP: functional implications.

Abstract

The modulation of voltage-dependent calcium currents strongly affects the firing pattern of central neurons. Changes in the intrinsic firing properties of mammalian globus pallidus cells (external pallidus in humans) are indicated as underlying the development of movement disorders. Pallidal neurons receive an excitatory input from the subthalamus, supposed to activate both ionotropic and metabotropic glutamate receptors. Since the activation of glutamate metabotropic receptors in rodent basal ganglia affects dopamine-mediated motor behaviors, we examined whether agonists at metabotropic sites modulate high-threshold calcium currents in pallidus. The broad agonist 1S,3R-ACPD produced a 22% reduction of calcium currents, which was mimicked by the group I agonist DHPG. These two responses were not additive; furthermore, the ACPD- and DHPG-mediated inhibition of high-threshold calcium currents were prevented by the cycloglycine MCPG, suggesting the involvement of a group I mGluR. The modulation was fast, saturating in less than 3 sec, partially voltage-dependent, in that about one-third was relieved by facilitation, and G-protein-mediated, since it was largely suppressed by NEM. Finally, the response was antagonized by omega-conotoxin-GVIA and omega-agatoxin-IVA, supporting the involvement of N- and P-type channels. The observed reduction of calcium signals might shape pallidal excitability, influencing the physiological balancing between globus pallidus and subthalamus. In pathological conditions such as parkinsonism, characterized by the putative increase of the endogenous release of glutamate from subthalamic neurons, the inhibition of high-threshold calcium currents in pallidus might modify the firing pattern of pallidal neurons and partially counteract the excitatory drive from STN. Nevertheless, the putative mGluR-induced reduction of intrinsic excitability might turn out to decrease the transmitter release from pallidal axon terminals, leading to further disinhibition of the output stations of the basal ganglia.