Alterations in neuregulin 1 (NRG1) signalling through the ErbB4 receptor have been linked to schizophrenia and bipolar disorder, yet the involvement of this pathway in the underlying pathogenesis is poorly understood. Corfas and colleagues have used a transgenic mouse model to show that the loss of ErbB-mediated signalling in oligodendrocytes leads to altered myelination and dopamine function and results in behavioural impairments relevant to psychiatric disorders.
Several disorders, including schizophrenia, bipolar disorder and anxiety, have been linked to abnormalities in the brain's white matter. In vitro studies have suggested a role for NRG1–ErbB4 signalling in the development of oligodendrocytes, the cells that myelinate CNS axons; however, the importance of this pathway in oligodendrocytes in vivo was unknown. To tackle this question, the authors used transgenic mice in which ErbB signalling was blocked by the expression of a dominant-negative ErbB4 receptor targeted to oligodendrocyte precursors and oligodendrocytes.
The authors showed that the loss of ErbB signalling in oligodendrocytes corresponded to a reduction in myelin sheath thickness in the corpus callosum and optic nerve, in which conduction velocity was also reduced. ErbB4 signalling has been linked to proliferation and survival of oligodendrocyte precursors. However, the number of oligodendrocyte precursors in the transgenic mice was normal, and there were actually more mature oligodendrocytes, indicating that a reduction in oligodendrocyte number did not cause reduced myelin thickness.
During myelination, oligodendrocytes extend and wrap multiple processes around their axonal targets. To determine whether the formation of these processes was defective, the authors examined the morphology of oligodendrocytes in the transgenic mice. Although the number of processes formed was normal, they branched less often, leading to a reduction in the overall process length available to ensheath the axons.
The authors tested the effects of reduced ErbB signalling on several behaviours relevant to psychiatric disorders. The transgenic mice exhibited reduced locomotor activity and exploration in novel open spaces and the elevated plus maze; these are effects that have been linked to anxiety, a symptom associated with schizophrenia and bipolar disorder. The animals displayed abnormal social behaviour in a resident-intruder test that assesses social interaction, taking longer than normal to initiate social contact with an intruder, an effect which is reminiscent of the social dysfunction observed in schizophrenia.
Many psychiatric disorders have been linked to altered dopamine signalling, prompting the authors to examine dompaminergic function in these mice. Consistent with the behavioural observations, they reported increased expression of the dopamine transporter (DAT) and dopamine D1-like receptors in the cortex, nucleus accumbens and striatum, resulting in increased sensitivity to dopamine release by amphetamine and to D1 agonists, effects that are also observed in some patients with schizophrenia.
This study demonstrates that subtle alterations in white matter structure can affect dopaminergic signalling and behaviour. It shows that ErbB signalling in oligodendrocytes regulates CNS myelination and provides a mechanistic link between this pathway and some symptoms of psychiatric disorders, in particular heightened anxiety. It would also be of interest to test the behaviour of these mice in other paradigms specific for schizophrenia or biopolar disorder. Nevertheless, the findings suggest that defective ErbB signalling during development might contribute to the dopaminergic dysfunction thought to underlie altered behaviour in psychiatric disorders.