Impact of neuregulin-1 on the pathophysiology of schizophrenia in human post-mortem studies

To a large extend schizophrenia has been shown to be heritable, with neuregulin-1 (NRG1) one of the candidate genes considered to play a role in the pathophysiology of the disorder. While several polymorphisms within this gene have been reported to be associated with schizophrenia, the impact of NRG1 risk genotypes on disturbed brain function and symptoms of the disease is unknown and might be elucidated using post-mortem studies. Neuregulins are signalling proteins and the NRG1 family encodes at least 15 different splice variants, classified into four isoforms. They play an important role in cell differentiation, migration, myelination and proliferation of oligodendrocytes and neurons. Dysfunction in these processes may be related to neurodevelopmental disturbances in schizophrenia. NRG1 isoforms are differentially expressed in relevant brain regions of schizophrenia patients such as the prefrontal cortex and hippocampus and may contribute to pathophysiological processes. Different NRG1 genotypes have been shown to influence gene expression of isoforms and the risk-associated variants are in primarily non-coding and promoter regions, probably operating by altering gene expression or splicing. In addition, NRG1 regulates the expression of the nicotinic acetylcholine receptor, and expression of the γ-aminobutyric acid (GABAA) and N-methyl-d-aspartate receptor in the brain. However, the contribution of NRG1 risk genotypes to expression of isoforms and cognitive or psychotic symptoms in patients remain to be investigated in prospective post-mortem studies. In animal models of ischemia/hypoxia, NRG1 has been shown to act as a therapeutic, neuroprotective agent and should be investigated in more detail in transgenic animal models.