Targeting Nitric Oxide Synthase 2 Reverses Learning Deficits in an Oligodendrocyte-Focused Model of Costello Syndrome

Myelination of axons by oligodendrocytes (OLs) greatly improves information processing in the brain; consequently, compromised myelin negatively impacts brain function. Young-adult Costello Syndrome (CS) patients present with learning disabilities and regression of psychomotor skills in correlation with abnormal brain white matter, delayed myelination, and dysmyelination. This suggests the involvement of OLs and myelin in abnormal brain physiology during and beyond development; however, the neuropathophysiology of CS remains poorly understood. Replacing the endogenous HRas gene with the CS-causing HRasG12V mutant gene in adult OLs (pHRasG/+ mice) induces ultrastructural myelin abnormalities; nonetheless, any functional impact is unknown. Here we show robust learning - but not memory - deficits in pHRasG/+ males and modest, delayed learning issues in females. Learning phenotypes are transient, likely involving compensatory responses from the OL lineage and microglia. Diffusion-weighted magnetic resonance imaging reveals region- and sex-dependent compromised myelin microstructure, coinciding with the peak of learning issues. Remarkably, pharmacological control of nitric oxide synthase 2 restores learning in male pHRasG/+ mice. Our study supports the notion that abnormal nitric oxide signaling in mature OLs affects learning, suggests a chronic impact of myelin-driven mechanisms in CS neuropathology, and proposes molecular targets with therapeutic potential for CS.