Alteration of synaptic transmission in the hippocampal‐mPFC pathway during extinction trials of context‐dependent fear memory in juvenile rat stress models

The medial prefrontal cortex (mPFC) has been proposed to be essential for extinction of fear memory, but its neural mechanism has been poorly understood. The present study examined whether synaptic transmission in the hippocampal‐mPFC pathway is related to extinction of context‐dependent fear memory in freely moving rats using electrophysiological approaches combined with behavioral analysis. Population spike amplitude in the mPFC was decreased during the first extinction trial by exposure to contextual fear conditioning. This synaptic inhibition was reversed by repeated extinction trials, accompanied by decreases in fear‐related freezing behavior. These results suggest that alteration of synaptic transmission in the hippocampal‐mPFC pathway is associated with the extinction processes of context‐dependent fear memory. Further experiments were performed to elucidate whether early postnatal stress alters the synaptic response in the mPFC during extinction trials using a juvenile stress model, based on our previous findings that early postnatal stress affects the behavioral response to emotional stress. Adult rats that previously were exposed to five footshocks (FS) (shock intensity, 0.5 mA; intershock interval, 28 seconds; shock duration, 2 seconds) at postnatal day 21 to 25 (week 3; 3W‐FS) exhibited impaired reversal of both inhibitory synaptic transmission and freezing behavior induced by repeated extinction trials. The neuronal and behavioral deficits observed in the 3W‐FS group were prevented by pretreatment with the serotonin_1A receptor agonist tandospirone (1 mg/kg, i.p.). These results indicate the possiblity that aversive stress exposure during the third postnatal week impaired extinction processes of context‐dependent fear memory. The deficits in extinction observed in the 3W‐FS group might be attributable to dysfunction of hippocampal‐mPFC neural circuits involving 5‐HT_1A receptor mechanisms. Synapse 63:805–813, 2009. © 2009 Wiley‐Liss, Inc.