Forced swim stress dynamically alters neural activity and bi-directionally modulates NMDA receptors in the prefrontal cortex

Repeated exposure to stress results in progressively divergent effects on cognitive behaviors that are dependent on the integrity of networks in the medial prefrontal cortex (mPFC). To investigate molecular mechanisms responsive to variable repetition of mild stress, we measured persistent neural activity, in vitro, from mPFC slices in mice that had been repetitively exposed to 10 minutes of forced swim stress for 3-10 days. 3-day short-term stress facilitated persistent neural activity by increasing event duration while 10 days suppressed event duration and amplitude. These dynamic changes were accompanied by a similar bi-directional modulation of the NMDA/AMPA receptor current ratio, an important synaptic mechanism for sustaining the persistency of neural activity. Specifically, short-term stress led to potentiated NMDA currents with slower decay kinetics, and extended stress produced smaller currents with faster decay. The inhibitory action of ifenprodil, a specific blocker of NR2B-containing NMDA receptors, was more effective in NMDA current suppression following light stress and less effective after longer stress compared to naive controls. Persistent activity and glutamate receptor balance in the neocortex have been linked to working memory and impulse control. Therefore, these results could provide insight for generating therapeutic strategies to prevent or reverse stress-induced cognitive deficits.