Aside from abnormal angiogenesis, dual endothelin-1/VEGF-signal peptide receptor-deficiency (DEspR^-/-) results in aberrant neuroepithelium and neural tube differentiation, thus elucidating DEspR's role in neurogenesis. With 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 hippocampal-dependent visuo-spatial and associative learning, and induced non-inflammatory 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, mTOR, and dephosphorylation of known autophagy inducers. Altogether, 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.