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.

Direct Interaction and Functional Coupling between Metabotropic Glutamate Receptor Subtype 1 and Voltage-sensitive Cav2.1 Ca2+ Channel

“…The inhibition of P/Q-type Ca 2ϩ channels by group 1 mGluRs has been reported in several neuronal cells as well as heterologously expressing cells (30,31,55). This investigation has indicated that mGluR1a inhibits Ca v 2.1 Ca 2ϩ channels in both ligand-dependent and ligand-independent manners, which are mediated by the mechanisms of the membrane-delimited G i /G o coupling and the physical coupling between the two proteins, respectively.…”

“…The coincident rise in [Ca 2ϩ ] i is important for integrating synaptic inputs to PNs (2,28,29). In contrast, the stimulation of group 1 mGluRs has been shown to inhibit P/Q-type Ca 2ϩ channels in cortical and globus pallidus neurons (30,31). However, neither temporally regulated mechanisms of mGluR1-mediated P/Qtype Ca 2ϩ channel modulation nor the physical interaction between mGluR1 and P/Q-type Ca 2ϩ channels have been addressed yet.…”

Down‐regulation of metabotropic glutamate receptor 1α in globus pallidus and substantia nigra of parkinsonian monkeys

“…An additional observation in the present study is that mGluR1 regulates the activity of pallidal neurons in normal awake monkeys. No in vivo experiments have so far been conducted to examine the contribution of mGluR1 to the behavior of pallidal neurons, nor have data from in vitro experiments extensively been available (Stefani et al ., 1998; Poisik et al ., 2003). Our extracellular unit recordings have revealed that DHPG (an agonist of group I mGluRs) significantly increases the spontaneous firing rate of pallidal neurons.…”

Activity Patterns in a Model for the Subthalamopallidal Network of the Basal Ganglia

“…I L , I K (Baranauskas et al, 1999;Hernandez-Pineda et al, 1999), I Na , I C a (Surmeier et al, 1994;Stefani et al, 1998), and I AHP are modeled with the same formulas and equations given above for the STN cells, whereas the low-threshold calcium current takes a simpler form: (Baranauskas et al, 1999). These parameters were selected to match the data for spontaneous firing patterns, rebound response to offset of hyperpolarization, spike frequency adaptation, and frequency -intensity curves obtained from the study of GPe cells in slices (K ita and K itai, 1991;Nambu and L linãs, 1994;Cooper and Stanford, 2000).…”