Pan-ErbB inhibition impairs cognition via disrupting myelination and aerobic glycolysis in oligodendrocytes.

White matter (WM) abnormalities are an emerging feature of schizophrenia, yet the underlying pathophysiological mechanisms are largely unknown. Disruption of ErbB signaling, which is essential for peripheral myelination, has been genetically associated with schizophrenia and WM lesions in schizophrenic patients. However, the roles of ErbB signaling in oligodendrocytes remain elusive. Here, we used an in vivo pan-ErbB inhibition strategy and demonstrated the functions of endogenous ErbB receptors in oligodendrocytes. Through analyses of the cellular, histological, biochemical, behavioral, and electrophysiological differences in mice with manipulated ErbB activities in oligodendrocytes at different differentiation stages, we found that ErbB signaling regulates myelination and aerobic glycolysis in oligodendrocytes, and both functions are required for working memory. ErbB inhibition in oligodendrocytes at early differentiation stages induces hypomyelination by suppressing the myelinating capacity of newly formed oligodendrocytes. In contrast, ErbB inhibition in mature oligodendrocytes alters neither myelination nor oligodendrocyte numbers, but accelerates axonal conduction decline under energy stress. Mechanistically, ErbB inhibition attenuates K-Ras activities, leading to the reduced expression of lactate dehydrogenase A that promotes aerobic glycolysis in mature oligodendrocytes. Supplementation of L-lactate restores axonal conduction and working memory capacity that are suppressed by ErbB inhibition in mature oligodendrocytes. These findings emphasize the indispensable roles of ErbB signaling in WM integrity and function and provide insights into the multifaceted contributions of WM abnormalities to cognitive impairment.