Structural brain abnormalities in endothelial nitric oxide synthase‐deficient mice revealed by high‐resolution magnetic resonance imaging

Abstract

Introduction: Endothelial nitric oxide synthase (eNOS) produces nitric oxide, which is essential for a variety of physiological functions in the brain. Previous work has demonstrated the detrimental effects of eNOS deficiency on brain function in male eNOS knockout (eNOS KO) mice. However, the effect of eNOS deficiency on brain structure and any association between these effects and sex is unknown.Methods: This study used three-dimensional high-resolution ex vivo magnetic resonance imaging and behavioral tests of anxiety and cognitive performance to investigate structure-function relationships in the brain of female and male eNOS KO mice in young adulthood.Results: While there were no differences in anxiety-like behavior or locomotion, there was a sex-specific deficit in contextual fear memory retention in male, but not in female, eNOS mice compared to wild-type controls. Moreover, we found that eNOS deficiency induced changes in multiple brain regions that are involved in learning and fear memory including the hippocampus, amygdala, hypothalamus, and areas of the cortex. Several of these MRI-detectable neuroanatomical changes were dependent on sex. Conclusion:The observation that eNOS deficiency impacts brain structure at an early age demonstrates the importance of eNOS for healthy brain development.

Cerebrovascular Endothelial Dysfunction: Role of BACE1

“…9,61 Structural alterations detected in the brains of eNOS −/− mice provide an additional explanation for observed behavioral impairments. 62 Of particular interest to this review, more recent studies designed to define cellular localization of BACE1 in the cerebrovascular endothelium indicate that in BBB, BACE1 is predominantly localized in the abluminal cell membrane. Indeed, abluminal levels of BACE1 protein are ≈2.5 higher as compared with levels detected in the luminal membrane of endothelial cells 34 (Figure 1).…”

“…9,61 Structural alterations detected in the brains of eNOS −/− mice provide an additional explanation for observed behavioral impairments. 62…”