ICER-Controlled inhibitory plasticity of amygdala engram neurons regulates fear memory precision

Abstract

Abstract Fear discrimination—the ability to distinguish threatening stimuli from non-threatening ones—is an essential adaptive behavior, yet the neural mechanisms underlying individual differences in discrimination precision remain unclear. Here, we show that parvalbumin-positive interneuron (PV-IN)-mediated feedforward inhibition to fear engram neurons (ENs) in the lateral amygdala is selectively enhanced following auditory fear conditioning, driven by increased postsynaptic expression of α1 subunit (Gabra1)-containing GABA A receptors. Disruption of PV-IN activity during fear retrieval—via optogenetic or chemogenetic inhibition—or selective induction of inhibitory long-term depression at PV → EN synapses impaired fear discrimination, increasing freezing to novel tones while sparing responses to the conditioned stimulus. Mechanistically, we identify inducible cAMP early repressor (ICER) as a transcriptional regulator that limits inhibitory plasticity by downregulating Gabra1 expression, thereby promoting fear generalization. These findings establish a previously unrecognized form of inhibitory synaptic plasticity that governs the precision of fear memory and suggest potential therapeutic targets for maladaptive fear overgeneralization in disorders such as post-traumatic stress disorder.