Uncoupling nNOS-PSD-95 in the ACC can inhibit contextual fear generalization

A typical feature of the contextual fear memory is increased fear generalization with time. Though much attention has been given to the neural structures that underlie the long-term consolidation of a contextual fear memory, the molecular mechanisms regulating fear generalization remain unclear. We observed that retrieval of contextual fear in a novel context at a remote time point increased coupling of neuronal nitric oxide synthase (nNOS) with postsynaptic density-95 (PSD-95) and c-Fos expression in the anterior cingulate cortex (ACC). Disrupting nNOS-PSD-95 coupling in the ACC decreased the expression of Histone deacetylase 2 (HDAC2), and inhibited contextual fear generalization at a remote time point. Together, our findings reveal nNOS-PSD-95 interaction in the ACC could be a promising target to prevent or reverse contextual fear generalization. •Contextual fear generalization up-regulated nNOS-PSD-95 coupling and HDAC2 expression.•Uncoupling nNOS-PSD-95 in the ACC inhibited fear generalization and reduced HDAC2 expression.•Knocking down the HDAC2 expression in the ACC could inhibit fear generalization.•nNOS-PSD-95 coupling could be a valuable target for the treatment of PTSD.