Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model

Abstract

Globus pallidus externa (GPe) is a nucleus in the basal ganglia circuitry involved in the control of movement. Recent studies have demonstrated a critical role of GPe cell types in Parkinsonism. Specifically increasing the function of parvalbumin (PV) neurons in the GPe has been found to facilitate motor function in a mouse model of Parkinson’s disease (PD). The knowledge of contribution of NMDA receptors to GPe function is limited. Here, we demonstrate that fast spiking neurons in the GPe express NMDA receptor currents sensitive to GluN2C/GluN2D-selective inhibitors and glycine site agonist with higher efficacy at GluN2C-containing receptors. Furthermore, using a novel reporter model, we demonstrate the expression of GluN2C subunits in PV neurons in the GPe which project to subthalamic nuclei. GluN2D subunit was also found to localize to PV neurons in GPe. Ablation of GluN2C subunit does not affect spontaneous firing of fast spiking neurons. In contrast, facilitating the function of GluN2C-containing receptors using glycine-site NMDA receptor agonists, D-cycloserine (DCS) or AICP, increased the spontaneous firing frequency of PV neurons in a GluN2C-dependent manner. Finally, we demonstrate that local infusion of DCS or AICP into the GPe improved motor function in a mouse model of PD. Together, these results demonstrate that GluN2C-containing receptors and potentially GluN2D-containing receptors in the GPe may serve as a therapeutic target for alleviating motor dysfunction in PD and related disorders.

Derivatives of (R)-3-(5-Furanyl)carboxamido-2-aminopropanoic Acid as Potent NMDA Receptor Glycine Site Agonists with GluN2 Subunit-Specific Activity

“…32 Moreover, the administration of DCS or AICP into the globus pallidus externa (GPe) was shown to improve the motor function in a mouse model of Parkinson's disease. 33 These observations demonstrate the potential for GluN2-specific Gly site agonists as modulators of NMDA receptors. Apart from AICP, analogues 6 and 7 are GluN1/2C superagonists with moderate potencies (EC 50 = 1.97 and 0.32 μM at GluN1/2C, respectively) and different agonist efficacy profiles across NMDA receptor subtypes compared to AICP.…”

“…The nRT neurons are enriched with GluN2C-containing NMDA receptors that are proposed to regulate corticothalamic and thalamocortical communication . Moreover, the administration of DCS or AICP into the globus pallidus externa (GPe) was shown to improve the motor function in a mouse model of Parkinson’s disease . These observations demonstrate the potential for GluN2-specific Gly site agonists as modulators of NMDA receptors.…”

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…In the spinal cord, GluN2C was weakly detected in the dorsal horn and nonneuronal cells in white and gray matter in the lumbar region (Tolle et al, 1993;Sundstrom et al, 1997;Shibata et al, 1999;Akesson et al, 2000) as well as the ventral horn early in postnatal development (Stegenga and Kalb, 2001), but was not detectable in the cervical spinal cord (Watanabe et al, 1994). Functional studies utilizing GluN2C-selective pharmacology support neuronal expression in the cerebellum, thalamus, and globus pallidus (Fernandez et al, 2017;Bhattacharya et al, 2018;Liu et al, 2019bLiu et al, , 2021.…”

GluN2C/D-containing NMDA receptors enhance temporal summation and increase sound-evoked and spontaneous firing in the inferior colliculus

“…We found that 10 ms glutamate puffs reliably elicited EPSCs in VIP neurons (Figure 2B). We next performed puffs in the presence of 1.5 µM PPDA, a GluN2C/D-selective antagonist (Lozovaya et al, 2004;Li et al, 2020;Jing et al, 2022), and then in the presence of 20 µM CIQ, a GluN2C/D-selective positive allosteric modulator (Feng et al, 2014;Zhang et al, 2014;Nouhi et al, 2018;Liu et al, 2021). PPDA significantly decreased the amplitude (LMM: β = -29.95, p = 1.44e-07), halfwidth (β = -33.79, p = 2.85e-09), rise time (β = -23.71, p = 1.64e-06) and decay time constant (β = -36.78, p = 2.08e-05) of the elicited EPSCs, while CIQ significantly enhanced the amplitude (β = 24.13, p = 1.69e-05) and halfwidth (β = 16.88, p = 0.0017) (Figure 2C,D).…”