title: Sex-specific hippocampus-dependent cognitive deficits and increased neuronal autophagy in DEspR haploinsufficiency in mice.
abstract: Aside from abnormal angiogenesis, dual endothelin-1/VEGF signal peptide-activated receptor deficiency (DEspR(-/-)) results in aberrant neuroepithelium and neural tube differentiation, thus elucidating DEspR's role in neurogenesis. With the emerging importance of neurogenesis in adulthood, we tested the hypothesis that nonembryonic-lethal DEspR haploinsufficiency (DEspR(+/-)) perturbs neuronal homeostasis, thereby facilitating aging-associated neurodegeneration. Here we show that, in male mice only, DEspR-haploinsufficiency impaired hippocampus-dependent visuospatial and associative learning and induced noninflammatory spongiform changes, neuronal vacuolation, and loss in the hippocampus, cerebral cortex, and subcortical regions, consistent with autophagic cell death. In contrast, DEspR(+/-) females exhibited better cognitive performance than wild-type females and showed absence of neuropathological changes. Signaling pathway analysis revealed DEspR-mediated phosphorylation of activators of autophagy inhibitor mammalian target of rapamycin (mTOR) and dephosphorylation of known autophagy inducers. Altogether, the data demonstrate DEspR-mediated diametrical, sex-specific modulation of cognitive performance and autophagy, highlight cerebral neuronal vulnerability to autophagic dysregulation, and causally link DEspR haploinsufficiency with increased neuronal autophagy, spongiosis, and cognitive decline in mice.
authors.affiliation: Department of Medicine, Section of Molecular Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Victoria L M
authors.initials: VL
authors.lastname: Herrera
authors.forename: Julius L
authors.initials: JL
authors.lastname: Decano
authors.forename: Pia
authors.initials: P
authors.lastname: Bagamasbad
authors.forename: Timothy
authors.initials: T
authors.lastname: Kufahl
authors.forename: Martin
authors.initials: M
authors.lastname: Steffen
authors.forename: Nelson
authors.initials: N
authors.lastname: Ruiz-Opazo
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D001522:Behavior, Animal / Q000502:physiology; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011945:Receptors, Angiotensin / Q000235:genetics; D017466:Receptors, Endothelin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D012919:Social Behavior
chemical_list: D011945:Receptors, Angiotensin; D017466:Receptors, Endothelin
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