S-nitrosylation of Dexras1 attenuates fear memory generalization in the infralimbic cortex

Fear memory generalization is a fundamental hallmark of post-traumatic stress disorder (PTSD) that enables animals to use past experience to adapt to changing conditions. The infralimbic cortex (IL) is implicated in suppressing generalized fear, but the underlying molecular mechanisms remain unknown. Here, we demonstrate that S-nitrosylation of Dexras1 (SNO-Dexras1) in the IL drives fear generalization. Dexras1 is activated by nitric oxide (NO) donors as well as by N-methyl-D-aspartic acid (NMDA) receptor-stimulated NO synthesis in cortical neurons. It is found that the level of SNO-Dexras1 is significantly increased in the IL of generalized mice and downregulation of SNO-Dexras1 attenuates fear generalization. Mechanistically, inhibition of SNO-Dexras1 increases the expression of phosphorylated extracellular regulated protein kinases (pERK) and brain derived neurotrophic factor (BDNF), implicating synaptic remodeling in the IL. Our study reveals a key role of SNO-Dexras1 in the fear generalization, which may provide a potential therapeutic strategy for PTSD.