Astrocytic NMDA Receptors in the Basolateral Amygdala Contribute to Facilitation of Fear Extinction

• Published in: The international journal of neuropsychopharmacology Vol. 24; no. 11; pp. 907 - 919
• Main Authors: Shelkar, Gajanan P, Liu, Jinxu, Dravid, Shashank M
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 01-11-2021
• Subjects: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - metabolism; Amygdala (Brain); Amygdala - drug effects; Animals; Anxiety; Astrocytes; Astrocytes - metabolism; Basolateral Nuclear Complex - metabolism; Care and treatment; Conditioning, Psychological - drug effects; Cycloserine - pharmacology; Excitatory Amino Acid Agonists - pharmacology; Extinction (Psychology); Extinction, Psychological - drug effects; Fear; Fear - drug effects; Health aspects; Methyl aspartate; Mice; Physiological aspects; Psychological aspects; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - metabolism; Regular s; Synaptic Transmission - drug effects; United States; GluN2C-containing NMDA receptors; Astrocytic NMDA receptors; basolateral amygdala; fear extinction
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1093/ijnp/pyab055

Abstract
Background
Enhancement of N-methyl-D-aspartate (NMDA) receptor function using glycine-site agonist D-cycloserine is known to facilitate fear extinction, providing a means to augment cognitive behavioral therapy in anxiety disorders. A novel class of glycine-site agonists has recently been identified, and we have found that the prototype, AICP, is more effective than D-cycloserine in modulating neuronal function.
Methods
Using novel glycine-site agonist AICP, local infusion studies, and genetic models, we elucidated the role of GluN2C-containing receptors in fear extinction.
Results
We tested the effect of intracerebroventricular injection of AICP on fear extinction and found a robust facilitation of fear extinction. This effect was dependent on GluN2C subunit, consistent with superagonist action of AICP at GluN2C-containing receptors. Local infusion studies in wild-type and GluN2C knockout mice suggested that AICP produces its effect via GluN2C-containing receptors in the basolateral amygdala (BLA). Furthermore, consistent with astrocytic expression of GluN2C subunit in the amygdala, we found that AICP did not facilitate fear extinction in mice with conditional deletion of obligatory GluN1 subunit from astrocytes. Importantly, chemogenetic activation of astrocytes in the basolateral amygdala facilitated fear extinction. Acutely, AICP was found to facilitate excitatory neurotransmission in the BLA via presynaptic GluN2C-dependent mechanism. Immunohistochemical studies suggest that AICP-mediated facilitation of fear extinction involves synaptic insertion of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor GluA1 subunit.
Conclusion
These results identify a unique role of astrocytic NMDA receptors composed of GluN2C subunit in extinction of conditioned fear memory and demonstrate that further development of recently identified superagonists of GluN2C-containing receptors may have utility for anxiety disorders.