Early life stress impairs fear memory and synaptic plasticity; a potential role for GluN2B.

Programming of the brain by early life stress has been associated with alterations in structure and function of the dorsal hippocampus. Yet, the underlying molecular mechanisms remain largely elusive. In this study, we examined the effects of early life stress (ELS) - by housing mouse dams with limited nesting and bedding material from postnatal days 2-9 and examined in 6 month old offspring; 1) auditory fear conditioning, 2) expression of the hippocampal N-methyl-d-aspartate receptor (NMDA-R) subunits 2A and 2B (GluN2A, GluN2B), and expression of PSD-95 and synaptophysin, and 3) short- and long-term (LTP) synaptic plasticity. Given its critical role in NMDA receptor function and synaptic plasticity, we further examined the role of GluN2B in effects of ELS on synaptic plasticity and fear memory formation. We demonstrate that ELS impaired fear memory in 6 month old mice and decreased hippocampal LTP as well as the paired-pulse ratio (PPR). ELS also reduced hippocampal GluN2B expression. Interestingly, pharmacological blockade of GluN2B with the selective antagonist Ro25 6981 was less effective to reduce synaptic plasticity in ELS mice, and was also ineffective to impair memory retrieval in ELS mice. These studies suggest that ELS reduces hippocampal synaptic plasticity and fear memory formation and hampers GluN2B receptor function. As such, GluN2B may provide an important target for future strategies to prevent lasting ELS effects on cognition.