PMID- 18780760
OWN - NLM
STAT- MEDLINE
DCOM- 20090128
LR  - 20211020
IS  - 1531-2267 (Electronic)
IS  - 1094-8341 (Print)
IS  - 1094-8341 (Linking)
VI  - 35
IP  - 3
DP  - 2008 Nov 12
TI  - Sex-specific hippocampus-dependent cognitive deficits and increased neuronal 
      autophagy in DEspR haploinsufficiency in mice.
PG  - 316-29
LID - 10.1152/physiolgenomics.00044.2008 [doi]
AB  - 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.
FAU - Herrera, Victoria L M
AU  - Herrera VL
AD  - Department of Medicine, Section of Molecular Medicine, Boston University School 
      of Medicine, Boston, Massachusetts 02118, USA.
FAU - Decano, Julius L
AU  - Decano JL
FAU - Bagamasbad, Pia
AU  - Bagamasbad P
FAU - Kufahl, Timothy
AU  - Kufahl T
FAU - Steffen, Martin
AU  - Steffen M
FAU - Ruiz-Opazo, Nelson
AU  - Ruiz-Opazo N
LA  - eng
GR  - HL-69937/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080909
PL  - United States
TA  - Physiol Genomics
JT  - Physiological genomics
JID - 9815683
RN  - 0 (Receptors, Angiotensin)
RN  - 0 (Receptors, Endothelin)
SB  - IM
MH  - Animals
MH  - Autophagy/genetics/*physiology
MH  - Behavior, Animal/physiology
MH  - Cognition Disorders/*genetics/pathology/physiopathology
MH  - Female
MH  - Hippocampus/*metabolism/pathology
MH  - Male
MH  - Maze Learning/physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mutation
MH  - Neurons/*metabolism/pathology
MH  - Receptors, Angiotensin/genetics
MH  - Receptors, Endothelin/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Sex Factors
MH  - Social Behavior
PMC - PMC2585022
EDAT- 2008/09/11 09:00
MHDA- 2009/01/29 09:00
PMCR- 2009/11/01
CRDT- 2008/09/11 09:00
PHST- 2008/09/11 09:00 [pubmed]
PHST- 2009/01/29 09:00 [medline]
PHST- 2008/09/11 09:00 [entrez]
PHST- 2009/11/01 00:00 [pmc-release]
AID - 00044.2008 [pii]
AID - PG-00044-2008 [pii]
AID - 10.1152/physiolgenomics.00044.2008 [doi]
PST - ppublish
SO  - Physiol Genomics. 2008 Nov 12;35(3):316-29. doi: 
      10.1152/physiolgenomics.00044.2008. Epub 2008 Sep 9.