Decreased Neuregulin 1 C-terminal fragment in Brodmann's area 6 of patients with schizophrenia.

Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. A decrease in NRG1-ErbB4 signalling has also been associated with the disease. β-amyloid precursor protein-cleaving enzyme (BACE1) processes type III NRG1 precursor, a major neuregulin variant expressed in the brain, to release NRG1 fragments that trigger signalling events and activation of neurotransmitter receptors. Experimental evidence suggests that muscarinic acetylcholine receptors (CHRM) regulate BACE1 expression. Having recently shown that CHRM1 levels are decreased selectively in frontal cortex regions of a subpopulation of schizophrenic patients (muscarinic receptor deficit schizophrenia, MRDS) we aimed to compare the protein expression of BACE1 and NRG1 in the agranular frontal cortex Brodmann's area 6 of SCZ subjects with normal levels of CHRM1 (N=19), MRDS (N=20), and age/gender-matched non-psychiatric (healthy) controls (HC; N=20). Western blot analysis of post-mortem samples showed that the levels of BACE1 and full-length NRG1 precursor (130kDa) did not differ significantly between the three groups. In contrast, the levels of the NRG1 C-terminal fragment (NRG1-CTF) were decreased by approximately 50% in both schizophrenic groups compared to the HC group (p<0.0027). The ratio of NRG1-CTF versus NRG1 precursor was significantly reduced in the SCZ groups compared to the HC group (p=0.051). There was no correlation between the levels of either full-length NRG1, NRG1-CTF, or BACE1 and the final recorded doses of antipsychotic drugs for the subjects with schizophrenia. A positive correlation was found between BACE1 and full-length NRG1 precursor in the HC group (r2=0.671, p<0.001) but not in the schizophrenic groups. These data suggest that the proteolytic processing of NRG1 is impaired in schizophrenia.