Plasticity of NMDA Receptors at Ventral Hippocampal Synapses in the Infralimbic Cortex Regulates Cued Fear

Abstract

The medial prefrontal cortex (mPFC) processes contextual information from the hippocampus to generate appropriate fear responses. In rodents, one path for sending contextual information to the mPFC is via the direct projections from the ventral hippocampus (vHC) to the infralimbic cortex (IL). Plasticity in the synaptic communication from the vHC to the IL could contribute to the behavioral changes produced by the acquisition and extinction of conditioned fear. To examine this possibility, we used optogenetic stimulation of vHC synapses in brain slices from trained rats. We found that fear acquisition reduced NMDA receptor (NMDAR) currents at vHC synapses onto IL pyramidal neurons. The depression of NMDAR currents reversed more efficiently after extinction in the conditioning context than extinction in a novel context. Moreover, a cohort of animals that exhibited poor extinction retrieval failed to reverse the plasticity induced by fear conditioning. In addition, ex vivo application of brain-derived neurotrophic factor, which is known to simulate extinction in IL, reversed this conditioning-induced plasticity mimicking extinction. Therefore, we have identified a novel mechanism that modulates conditioned fear via changes in NMDAR current at vHC synapses onto IL pyramidal neurons. Disruption of this mechanism could contribute to the abnormal contextual modulation of fear seen in posttraumatic stress disorder (PTSD).

Significance Statement Contextual information processing by the medial prefrontal cortex is critical for appropriate behavioral responses. Using optogenetics in brain slices, we found that acquisition of conditioned fear depressed NMDA receptor currents at ventral hippocampal synapses in the infralimbic cortex (IL) and extinction reversed the depression. BDNF could also reverse the conditioning-induced depression mimicking extinction. In contrast, animals with impaired fear extinction recall, a PTSD-like phenotype, failed to reverse the conditioning-induced changes. Our findings suggest that conditioned fear responses are modulated by changes in NMDAR current at ventral hippocampal synapses in IL and suggest a novel mechanism that could contribute to impaired contextual modulation of fear seen in patients with PTSD.