title: Forebrain CRF₁ modulates early-life stress-programmed cognitive deficits.
abstract: Childhood traumatic events hamper the development of the hippocampus and impair declarative memory in susceptible individuals. Persistent elevations of hippocampal corticotropin-releasing factor (CRF), acting through CRF receptor 1 (CRF₁), in experimental models of early-life stress have suggested a role for this endogenous stress hormone in the resulting structural modifications and cognitive dysfunction. However, direct testing of this possibility has been difficult. In the current study, we subjected conditional forebrain CRF₁ knock-out (CRF₁-CKO) mice to an impoverished postnatal environment and examined the role of forebrain CRF₁ in the long-lasting effects of early-life stress on learning and memory. Early-life stress impaired spatial learning and memory in wild-type mice, and postnatal forebrain CRF overexpression reproduced these deleterious effects. Cognitive deficits in stressed wild-type mice were associated with disrupted long-term potentiation (LTP) and a reduced number of dendritic spines in area CA3 but not in CA1. Forebrain CRF₁ deficiency restored cognitive function, LTP and spine density in area CA3, and augmented CA1 LTP and spine density in stressed mice. In addition, early-life stress differentially regulated the amount of hippocampal excitatory and inhibitory synapses in wild-type and CRF₁-CKO mice, accompanied by alterations in the neurexin-neuroligin complex. These data suggest that the functional, structural and molecular changes evoked by early-life stress are at least partly dependent on persistent forebrain CRF₁ signaling, providing a molecular target for the prevention of cognitive deficits in adults with a history of early-life adversity.
authors.affiliation: Max Planck Institute of Psychiatry, 80804 Munich, Germany. wangxd@mpipsykl.mpg.de
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Wang
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rammes
authors.forename: Igor
authors.initials: I
authors.lastname: Kraev
authors.forename: Miriam
authors.initials: M
authors.lastname: Wolf
authors.forename: Claudia
authors.initials: C
authors.lastname: Liebl
authors.forename: Sebastian H
authors.initials: SH
authors.lastname: Scharf
authors.forename: Courtney J
authors.initials: CJ
authors.lastname: Rice
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Jan M
authors.initials: JM
authors.lastname: Deussing
authors.forename: Tallie Z
authors.initials: TZ
authors.lastname: Baram
authors.forename: Michael G
authors.initials: MG
authors.lastname: Stewart
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Müller
authors.forename: Mathias V
authors.initials: MV
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D003072:Cognition Disorders / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D049229:Dendritic Spines / Q000473:pathology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000166:cytology; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D016548:Prosencephalon / Q000378:metabolism*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013037:Spatial Behavior / Q000502:physiology; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D000099052:CRF Receptor, Type 1
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; C527193:Nrxn1 protein, mouse; D018019:Receptors, Corticotropin-Releasing Hormone; C098004:neuroligin 3; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone