A New Beginning for a Broken Mind: Balancing Neuregulin 1 Reverses Synaptic Dysfunction

Schizophrenia is a severe mental illness that affects approximately 1% of the population worldwide. Genetic factors play a major role in the etiology of schizophrenia, with an estimated heritability of around 80%. Genetic variation in Neuregulin 1 (NRG1) has been repeatedly linked to the disorder in multiple human populations. In particular, more than 80 single nucleotide polymorphisms localized in noncoding regions of this gene have been identified (Mei and Xiong, 2008). These observations led to the hypothesis that expression of NRG1 might be altered in schizophrenia. Alternative splicing of NRG1 generates more than 30 isoforms classified in six different types (I to VI) depending on their structure (Mei and Xiong, 2008). They all share an epidermal growth factor (EGF)like domain, which is required for the activation of several members of the ErbB family of receptor tyrosine kinases. In schizophrenia, the expression of particular isoforms of NRG1 seems altered, although reports are contradictory. For example, several studies reported a reduction in the levels of the isoform 1 alpha of NRG1 in the brain of schizophrenia patients (e.g., Bertram et al., 2007), while others showed elevated levels of NRG1 in a particular risk haplotype (e.g., Weickert et al., 2012). Consistent with this later view, several other studies have shown increased NRG1 mRNA and protein levels in the hippocampus and prefrontal cortex of schizophrenia patients (Hashimoto et al., 2004; Petryshen et al., 2005). These contradictory findings have been surprisingly replicated in mice: both loss and gain of NRG1