Abstract
BackgroundNeuregulin 1 (NRG1) is a key candidate susceptibility gene for both schizophrenia (SCZ) and bipolar disorder (BPD). The function of the NRG1 transmembrane proteins is regulated by cleavage. Alteration of membrane bound-NRG1 cleavage has been previously shown to be associated with behavioral impairments in mouse models lacking expression of NRG1-cleavage enzymes such as BACE1 and gamma secretase. We sought to determine whether alterations in NRG1 cleavage and associated enzymes occur in patients with SCZ and BPD.Methodology/Principal FindingsUsing human postmortem brain, we evaluated protein expression of NRG1 cleavage products and enzymes that cleave at the external (BACE1, ADAM17, ADAM19) and internal (PS1-gamma secretase) sides of the cell membrane. We used three different cohorts (Controls, SCZ and BPD) and two distinct brain regions: BA9-prefrontal cortex (Controls (n = 6), SCZ (n = 6) and BPD (n = 6)) and hippocampus (Controls (n = 5), SCZ (n = 6) and BPD (n = 6)). In BA9, the ratio of the NRG1 N-terminal fragment relative to full length was significantly upregulated in the SCZ cohort (Bonferroni test, p = 0.011). ADAM17 was negatively correlated with full length NRG1 levels in the SCZ cohort (r = –0.926, p = 0.008). In the hippocampus we found significantly lower levels of a soluble 50 kDa NRG1 fragment in the two affected groups compared the control cohort (Bonferroni test, p = 0.0018). We also examined the relationship of specific symptomatology criteria with measures of NRG1 cleavage using the Bipolar Inventory of Signs and Symptoms Scale (BISS) and the Montgomery Åsberg Depression Rating Scale (MADRS). Our results showed a positive correlation between ADAM19 and psychosis (r = 0.595 p = 0.019); PS1 and mania (r = 0.535, p = 0.040); PS1 and depression (r = 0.567, p = 0.027) in BA9, and BACE1 with anxiety (r = 0.608, p = 0.03) in the hippocampus.Conclusion/SignificanceOur preliminary findings suggest region-specific alterations in NRG1 cleavage in SCZ and BPD patients. These changes may be associated with specific symptoms in these psychiatric disorders.
Highlights
Schizophrenia (SCZ) and bipolar disorder (BPD), two of the most severe psychiatric disorders, are complex disorders with both genetic and environmental underpinnings
In Brodmann’s area 9 (BA9), pH was found to correlate with ADAM17 (r = –0.523, p = 0.026); Neuregulin 1 (NRG1) N terminal fragment (NTF) (r = 0.530, p = 0.024) and NRG1 Full length (FL) (r = 0.487, p = 0.04); brain weight was shown to correlate with NRG1 FL (r = 0.473, p = 0.047)
Sex correlated with beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) levels (r = 0.563, p = 0.018) and race correlated with NTF (r = –0.541, p = 0.025); brain weight was shown to negatively correlate with BACE1 levels (r = –0.527, p = 0.030)
Summary
Schizophrenia (SCZ) and bipolar disorder (BPD), two of the most severe psychiatric disorders, are complex disorders with both genetic and environmental underpinnings. Our laboratory previously identified a novel missense polymorphism (V.L) in the transmembrane region of NRG1 that is associated with schizophrenia [17] This amino acid change has more recently been shown to impede gamma-secretase cleavage of the NRG1 CTF [9]. We analyzed symptoms experienced in the last week of life using scales of symptom severity such as the MINI [22] Bipolar Inventory of Signs and Symptoms Scale (BISS) [23] and the Montgomery Asberg Depression Rating Scale (MADRS) [24] These studies will shed light as to the role of NRG1 in development of SCZ and BPD. We sought to determine whether alterations in NRG1 cleavage and associated enzymes occur in patients with SCZ and BPD
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