Modulation of burst firing of neurons in nucleus reticularis of the thalamus by GluN2C-containing NMDA receptors

The GluN2C subunit of the NMDA receptor is enriched in the neurons in the nucleus reticularis of the thalamus (nRT), but its role in regulating their function is not well understood. We found that deletion of GluN2C subunit did not affect spike frequency in response to depolarizing current injection or hyperpolarization-induced rebound burst firing of nRT neurons. D-Cycloserine or CIQ (GluN2C/GluN2D positive allosteric modulator) did not affect the depolarization-induced spike frequency in nRT neurons. A newly identified highly potent and efficacious coagonist of GluN1/GluN2C NMDA receptors, AICP ((R)-2-amino-3-(4-(2-ethylphenyl)-1H-indole-2-carboxamido)propanoic acid), was found to reduce the spike frequency and burst firing of nRT neurons in wild type but not GluN2C knockout. This effect was potentially due to facilitation of GluN2C-containing receptors, because inhibition of NMDA receptors by AP5 did not affect spike frequency in nRT neurons. We evaluated the effect of intracerebroventricular injection of AICP. AICP did not affect basal locomotion or prepulse inhibition but facilitated MK-801induced hyperlocomotion. This effect was observed in wildtype but not in GluN2C knockout mice, demonstrating that AICP produces GluN2C-selective effects in vivo. Using a chemogenetic approach, we examined the role of nRT in this behavioral effect. G_q- or G_i-coupled DREADDs were selectively expressed in nRT neurons using Cre-dependent viral vectors and PV-Cre mouse line. We found that similar to AICP effect, activation of G_q- but not G_i-coupled DREADD facilitated MK-801-induced hyperlocomotion. Together, these results identify a unique role of GluN2C-containing receptors in the regulation of nRT neurons and suggest GluN2C-selective in vivo targeting of NMDA receptors by AICP.