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 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 co-agonist of GluN1/GluN2C NMDA receptors, AICP, was found to reduce the spike frequency and burst firing of nRT neurons in wildtype 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-801-induced 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. Gq or Gi 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 Gq but not Gi 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. SIGNIFICANCE STATEMENT: The nucleus reticularis of the thalamus composed of GABAergic neurons is termed as guardian of the gateway and is an important regulator of corticothalamic communication which may be impaired in autism, non-convulsive seizures and other conditions. We found that strong facilitation of tonic activity of GluN2C subtype of NMDA receptors using AICP, a newly identified glycine-site agonist of NMDA receptors, modulates the function of reticular thalamus neurons. AICP was also able to produce GluN2C-dependent behavioral effects <I>in vivo</I>. Together, these finding identify a novel mechanism and a pharmacological tool to modulate activity of reticular thalamic neurons in disease states. The American Society for Pharmacology and Experimental Therapeutics.