Sex-specific hippocampus-dependent cognitive deficits and increased neuronal autophagy in DEspR haploinsufficiency in mice.
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.
Herrera
Victoria L M
VL
Department of Medicine, Section of Molecular Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Decano
Julius L
JL
Bagamasbad
Pia
P
Kufahl
Timothy
T
Steffen
Martin
M
Ruiz-Opazo
Nelson
N
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
D011945:Receptors, Angiotensin; D017466:Receptors, Endothelin
Ann Neurol. 1997 Oct;42(4):604-12
9382472
Behav Neurosci. 1984 Oct;98(5):908-13
6487419
Nature. 2006 Jun 15;441(7095):880-4
16625205
Circ Res. 2007 May 25;100(10):1522-9
17446437
Autophagy. 2007 Sep-Oct;3(5):512-5
17643071
Histol Histopathol. 1997 Jan;12(1):25-31
9046040
Nat Rev Drug Discov. 2007 Apr;6(4):304-12
17396135
Hum Mol Genet. 2001 Jun 1;10(12):1243-54
11406606
Development. 1998 Mar;125(5):813-24
9449664
Mol Psychiatry. 1999 Sep;4(5):453-62
10523818
Physiol Genomics. 2006 Aug 16;26(3):172-9
16720678
Mol Med. 2004 Jan-Jun;10(1-6):36-44
15502881
Nature. 2004 Apr 15;428(6984):715-6
15085121
Neuron. 2003 Oct 9;40(2):401-13
14556717
Mol Med. 1998 Feb;4(2):96-108
9508787
J Neuropathol Exp Neurol. 2005 Feb;64(2):113-22
15751225
Atherosclerosis. 2004 Nov;177(1):9-18
15488860
Neurobiol Learn Mem. 2006 Jan;85(1):95-101
16214380
Cell. 2008 Jan 11;132(1):27-42
18191218
Physiol Behav. 1988;42(2):119-24
3368530
Genes Brain Behav. 2002 Jan;1(1):55-69
12886950
Autophagy. 2007 Sep-Oct;3(5):461-3
17471017
Curr Top Dev Biol. 2006;76:89-101
17118264
Nature. 1994 Apr 21;368(6473):703-10
8152482
Nat Protoc. 2006;1(2):848-58
17406317
Mamm Genome. 2004 Aug;15(8):648-62
15457344
Nature. 1982 Jun 24;297(5868):681-3
7088155
Nature. 1996 Apr 4;380(6573):439-42
8602242
Neurosci Biobehav Rev. 2004 Sep;28(5):463-83
15465135
Dev Cell. 2004 Apr;6(4):463-77
15068787
Neurosignals. 2008;16(1):75-84
18097162
Physiol Genomics. 2005 Nov 17;23(3):257-68
16293765
Neuroscience. 2003;122(1):213-28
14596862
J Neuropathol Exp Neurol. 2006 May;65(5):423-32
16772866
Proc Natl Acad Sci U S A. 1997 May 27;94(11):5837-42
9159161
Nature. 2006 Jun 15;441(7095):885-9
16625204
Cell Death Differ. 2007 May;14(5):887-94
17332773
Biochimie. 2008 Feb;90(2):313-23
17928127
Physiol Genomics. 2005 Jan 20;20(2):157-64
15561758
Int J Biochem Cell Biol. 2004 Dec;36(12):2473-90
15325586
Teratology. 1973 Jun;7(3):253-66
4807128
Cell. 1994 Dec 30;79(7):1267-76
8001159
Blood. 2007 Jun 1;109(11):4793-802
17272502
Neurosci Biobehav Rev. 2005 Jan;28(8):811-25
15642623
Am J Pathol. 2008 Feb;172(2):454-69
18187572
J Virol. 2003 Dec;77(23):12617-29
14610184
J Neurochem. 2007 Oct;103(1):259-75
17635673
Nature. 1996 Apr 4;380(6573):435-9
8602241
Nat Genet. 1997 Nov;17(3):280-4
9354790
J Neuropathol Exp Neurol. 1986 Mar;45(2):108-26
3512779
J Neurotrauma. 2008 Jul;25(7):785-94
18627256
Nat Genet. 2006 Feb;38(2):218-22
16429159
Int J Biochem Cell Biol. 2004 Dec;36(12):2563-73
15325593
Hypertension. 2004 Apr;43(4):797-802
14967836
Hippocampus. 1995;5(6):546-56
8646281
Eur J Neurosci. 2003 Aug;18(3):473-85
12911744
Nat Neurosci. 2000 Apr;3(4):404-8
10725932
Int J Biochem Cell Biol. 2004 Dec;36(12):2376-91
15325579
Int J Biochem Cell Biol. 2004 Dec;36(12):2392-404
15325580