Astrocytic NMDA receptors in the basolateral amygdala contribute to facilitation of fear extinction.

ABSTRACT:

Background

Enhancement of 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. Recently a novel class of glycine-site agonists have 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 wildtype and GluN2C knockout mice suggested that AICP produces its effect via GluN2C-containing receptors in the basolateral amygdala. 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 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.

SUBMITTER: Shelkar GP 

PROVIDER: S-EPMC8598288 | biostudies-literature |

REPOSITORIES: biostudies-literature