Dual regulation of glutamatergic transmission and cognition by stress in prefrontal cortex

Corticosterone, the major stress hormone, serves as a key controller for neuronal responses that underlie behavioral adaptation, as well as maladaptive changes that lead to cognitive and emotional disturbances in stress-related mental disorders. The molecular and cellular mechanisms underlying the complex actions of corticosteroid stress hormones are largely unknown. Here we demonstrate that acute versus chronic stress exerts opposite effects on glutamatergic transmission in prefrontal cortex (PFC), which leads to opposing effects on PFC-dependent cognitive functions. Acute stress induces synaptic potentiation by increasing surface delivery of N-methyl-D-aspartate (NMDA)-type and α-amino-3-hydroxy-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptor channels via glucocorticoid/serum- and glucocorticoid-inducible kinase (SGK)/Rab4 signaling, resulting in enhanced working memory performance. In contrast, repeated stress induces synaptic depression by increasing the ubiquitin/proteasome-mediated degradation of NMDA and AMPA receptor subunits, resulting in impaired recognition memory.