GluN3A excitatory glycine receptors control adult cortical and amygdalar circuits

• Published in: Neuron (Cambridge, Mass.) Vol. 110; no. 15; pp. 2438 - 2454.e8
• Main Authors: Bossi, Simon, Dhanasobhon, Dhanasak, Ellis-Davies, Graham C.R., Frontera, Jimena, de Brito Van Velze, Marcel, Lourenço, Joana, Murillo, Alvaro, Luján, Rafael, Casado, Mariano, Perez-Otaño, Isabel, Bacci, Alberto, Popa, Daniela, Paoletti, Pierre, Rebola, Nelson
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.08.2022; Elsevier; Cell Press
• Subjects: amygdala; cortex; fear; GluN3A; glycine; interneuron; Life Sciences; Neurobiology; Neurons and Cognition; neurotransmission; NMDA; receptors; somatostatin interneurons; tonic activation; cortex; tonic activation; amygdala; neurotransmission; receptors; glycine; somatostatin interneurons; NMDA; interneuron; GluN3A; fear
• ISSN: 0896-6273; 1097-4199; 1097-4199
• DOI: 10.1016/j.neuron.2022.05.016

GluN3A is an atypical glycine-binding subunit of NMDA receptors (NMDARs) whose actions in the brain are mostly unknown. Here, we show that the expression of GluN3A subunits controls the excitability of mouse adult cortical and amygdalar circuits via an unusual signaling mechanism involving the formation of excitatory glycine GluN1/GluN3A receptors (eGlyRs) and their tonic activation by extracellular glycine. eGlyRs are mostly extrasynaptic and reside in specific neuronal populations, including the principal cells of the basolateral amygdala (BLA) and SST-positive interneurons (SST-INs) of the neocortex. In the BLA, tonic eGlyR currents are sensitive to fear-conditioning protocols, are subject to neuromodulation by the dopaminergic system, and control the stability of fear memories. In the neocortex, eGlyRs control the in vivo spiking of SST-INs and the behavior-dependent modulation of cortical activity. GluN3A-containing eGlyRs thus represent a novel and widespread signaling modality in the adult brain, with attributes that strikingly depart from those of conventional NMDARs. [Display omitted] •In mice, GluN3A is expressed by SST-INs in the cortex and pyramidal neurons in the BLA•GluN3A assembles as excitatory glycine GluN1/GluN3A receptors (eGlyRs)•eGlyRs detect extracellular glycine levels and generate tonic excitatory currents•eGlyRs tune the function of SST-INs in cortex and alter the formation of fear memories in BLA Bossi et al. show that GluN3A subunits control the activity of selective neuronal populations in the adult mouse brain via the formation of excitatory glycine GluN1/GluN3A receptors (eGlyRs). Functional analysis reveals that eGlyRs regulate the recruitment of somatostatin-positive interneurons in the neocortex and participate in the stability of fear memories in the BLA.