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 molecular 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 hippocampal levels of synapse-related proteins. During the stress exposure, repeated blockade of glucocorticoid receptors (GRs) by daily administration of RU486 (100 µg g(-1) ) failed to attenuate postnatal stress-evoked synaptic impairments. Conversely, daily administration of the CRHR1 antagonist antalarmin hydrochloride (20 µg g(-1) ) in stressed pups normalized hippocampal protein levels of synaptophysin, postsynaptic density-95, nectin-1, and nectin-3, but not the N-methyl-d-aspartate 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, spinogenesis, and synapse formation, and that early interventions of this system may prevent stress-induced hippocampal maldevelopment.
Institute of Mental Health, Peking University, 100191, Beijing, China; Key Laboratory for Mental Health, Ministry of Health (Peking University), 100191, Beijing, China.
Xue-Mei
XM
Liao
Xiao-Dun
XD
Yang
Jiao
J
Jia
Ji-Tao
JT
Li
Xiao-Meng
XM
Xie
Yun-Ai
YA
Su
Mathias V
MV
Schmidt
Tian-Mei
TM
Si
Xiao-Dong
XD
Wang
D000818:Animals; D000831:Animals, Newborn; D015815:Cell Adhesion Molecules / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D003712:Dendrites / Q000473:pathology; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D006727:Hormone Antagonists / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D000075983:Nectins; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016708:Synaptophysin / Q000378:metabolism; D000099052:CRF Receptor, Type 1
D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D006727:Hormone Antagonists; D008565:Membrane Proteins; C000619015:Nectin1 protein, mouse; C000619017:Nectin3 protein, mouse; D000075983:Nectins; D009419:Nerve Tissue Proteins; D018019:Receptors, Corticotropin-Releasing Hormone; D016194:Receptors, N-Methyl-D-Aspartate; D016708:Synaptophysin; C098003:neuroligin 2; D015735:Mifepristone; D000099052:CRF Receptor, Type 1; D051528:Guanylate Kinases; D003345:Corticosterone
corticotropin-releasing hormone receptor 1; early-life stress; glucocorticoid receptors; hippocampus; synapse