Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders

TLDR

White‑matter abnormalities are linked to psychiatric disorders, and the NRG1‑erbB4 signaling pathway—genetically associated with schizophrenia and bipolar disorder—is essential for oligodendrocyte development. The study aimed to determine whether disrupting erbB signaling in oligodendrocytes affects their structure and function, thereby contributing to psychiatric disease. Transgenic mice were engineered to block erbB signaling specifically in oligodendrocytes, allowing in vivo assessment of its effects. Loss of erbB signaling in oligodendrocytes caused reduced myelin thickness, altered OL morphology, slowed axonal conduction, elevated dopamine receptor and transporter levels, and behavioral changes, linking white‑matter defects to dopaminergic dysfunction and neuropsychiatric phenotypes.

Abstract

Several psychiatric disorders are associated with white matter defects, suggesting that oligodendrocyte (OL) abnormalities underlie some aspects of these diseases. Neuregulin 1 (NRG1) and its receptor, erbB4, are genetically linked with susceptibility to schizophrenia and bipolar disorder. In vitro studies suggest that NRG1-erbB signaling is important for OL development. To test whether erbB signaling contributes to psychiatric disorders by regulating the structure or function of OLs, we analyzed transgenic mice in which erbB signaling is blocked in OLs in vivo. Here we show that loss of erbB signaling leads to changes in OL number and morphology, reduced myelin thickness, and slower conduction velocity in CNS axons. Furthermore, these transgenic mice have increased levels of dopamine receptors and transporters and behavioral alterations consistent with neuropsychiatric disorders. These results indicate that defects in white matter can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric disorders.