Tonic Activation of GluN2C/GluN2D-Containing NMDA Receptors by Ambient Glutamate Facilitates Cortical Interneuron Maturation

• Type of Material: Article
• Authors: Elizabeth Hanson, Tufts University; Moritz Armbruster, Tufts University; Lauren A. Lau, Tufts University; Mary E. Sommer, Tufts University; Zin-Juan Klaft, Tufts University; Sharon A. Swanger, Emory University; Stephen Traynelis, Emory University; Stephen J. Moss, Tufts University; Farzad Noubary, Northeastern University; Jayashree Chadchankar, Tufts University; Chris G. Dulla, Tufts University
• Language: English
• Date: 2019-05-08
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 2019 the authors. CC BY 4.0.
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.1392-18.2019
• Title of Journal or Parent Work: Journal of Neuroscience
• ISSN: 0270-6474
• Volume: 39
• Issue: 19
• Start Page: 3611
• End Page: 3626
• Grant/Funding Information: This work was supported by the Epilepsy Foundation to C.G.D., National Institute of Neurological Disease and Stroke R01-NS076885 to C.G.D., R56-NS076885 to C.G.D., NS036554 to S.F.T., Synapse Neurobiology Training Grant NINDS T32-NS061764 to E.H., and Tufts Center for Neuroscience Research P30 S047243.
• Keywords: DIFFERENTIAL EXPRESSION; Life Sciences & Biomedicine; RAT-BRAIN; PYRAMIDAL CELLS; Science & Technology; NMDA receptor; NEURONS; Neurosciences; developmental; GAMMA OSCILLATIONS; CORTEX; MESSENGER-RNAS; ambient glutamate; GABAERGIC INTERNEURONS; cortex; inhibition; PLASTICITY; cortical interneuron; Neurosciences & Neurology; SYNAPTICALLY RELEASED GLUTAMATE
• Research Categories: Biology, Neuroscience; Health Sciences, Pharmacology

Abstract

Developing cortical GABAergic interneurons rely on genetic programs, neuronal activity, and environmental cues to 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 contributes to, and is necessary for, the maturation of cortical interneurons. To test this 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 manipulate tonic 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.