Hanson, E; Armbruster, M; Lau, LA; Sommer, ME; Klaft, Z-J; Swanger, SA; Traynelis, SF; ... Dulla, CG; + view all Hanson, E; Armbruster, M; Lau, LA; Sommer, ME; Klaft, Z-J; Swanger, SA; Traynelis, SF; Moss, SJ; Noubary, F; Chadchankar, J; Dulla, CG; - view fewer (2019) Tonic Activation of GluN2C/GluN2D-Containing NMDA Receptors by Ambient Glutamate Facilitates Cortical Interneuron Maturation. The Journal of Neuroscience , 39 (19) pp. 3611-3626. 10.1523/JNEUROSCI.1392-18.2019.

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Abstract

Developing cortical GABAergic interneurons rely on genetic programs, neuronal activity, and environmental cuesto construct inhibitory circuits during early postnatal development. Disruption of these events can cause long-term changes in cortical inhibition and may be involved in neurological disorders associated with inhibitory circuit dysfunction. We hypothesized that tonic glutamate signaling in the neonatal cortex contributesto, and is necessary for,the maturation of cortical interneurons. Totestthis hypothesis, we used mice of both sexes to quantify extracellular glutamate concentrations in the cortex during development, measure ambient glutamate-mediated activation of developing cortical interneurons, and manipulatetonic glutamate signaling using subtype-specific NMDA receptor antagonists in vitro and in vivo. We report that ambient glutamate levels are high (100 nM) in the neonatal cortex and decrease (to 50 nM) during the first weeks of life, coincident with increases in astrocytic glutamate uptake. Consistent with elevated ambient glutamate, putative parvalbumin-positive interneurons in the cortex (identified using G42:GAD1-eGFP reporter mice) exhibit a transient, tonic NMDA current at the end of the first postnatal week. GluN2C/GluN2D-containing NMDA receptors mediate the majority of this current and contribute to the resting membrane potential and intrinsic properties of developing putative parvalbumin interneurons. Pharmacological blockade of GluN2C/GluN2D-containing NMDA receptors in vivo during the period of tonic interneuron activation, but not later, leads to lasting decreases in interneuron morphological complexity and causes deficits in cortical inhibition later in life. These results demonstrate that dynamic ambient glutamate signaling contributes to cortical interneuron maturation via tonic activation of GluN2C/ GluN2D-containing NMDA receptors

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