Blockade of corticotropin‐releasing hormone receptor 1 attenuates early‐life stress‐induced synaptic abnormalities in the neonatal hippocampus

Adult individuals with early stressful experience exhibit impaired hippocampal neuronal morphology, synaptic plasticity and cognitive performance. While our knowledge on the persistent effects of early-life stress on hippocampal structure and function and the underlying mechanisms has advanced over the recent years, the molec- ular basis of the immediate postnatal stress effects on hippocampal development remains to be investigated. Here, we reported that repeated blockade of corticotropin-releasing hormone receptor 1 (CRHR1) ameliorated postnatal stress-induced hippocampal synaptic abnormalities in neonatal mice. Following the stress exposure, pups with fragmented maternal care showed retarded dendritic outgrowth and spine formation in CA3 pyramidal neurons and reduced hippocam- pal levels of synapse-related proteins. During the stress exposure, repeated blockade of glucocorticoid receptors (GRs) by daily adminis- tration of RU486 (100 m gg 21 ) failed to attenuate postnatal stress- evoked synaptic impairments. Conversely, daily administration of the CRHR1 antagonist antalarmin hydrochloride (20 m gg 21 ) in stressed pups normalized hippocampal protein levels of synaptophysin, postsy- naptic density-95, nectin-1, and nectin-3, but not the N-methyl-D-aspar- tate receptor subunits NR1 and NR2A. Additionally, GR or CRHR1 antagonism attenuated postnatal stress-induced endocrine alterations but not body growth retardation. Our data indicate that the CRH- CRHR1 system modulates the deleterious effects of early-life stress on dendritic development, spinogene- sis, and synapse formation, and that early interven- tions of this system may prevent stress-induced hippocampal maldevelopment. V C 2014 Wiley Periodi- cals, Inc.