Reduction of dopamine-related transcription factors Nurr1 and NGFI-B in the prefrontal cortex in schizophrenia and bipolar disorders.

Abnormal cortical and subcortical dopaminergic activities are among the most consistent neuropathological findings in schizophrenia. The molecular mechanisms remain unspecified. NGFI-B and Nurr1 are two closely related transcription factors involved in dopaminergic cell differentiation, maturation, and apoptosis. NGFI-B knockout mice show attenuated behavioral response to dopamine receptor agonists, whereas Nurr1 knockout disrupts midbrain dopaminergic neuron development. To further understand the role of Nurr1 and NGFI-B in schizophrenia and bipolar disorders, we measured Nurr1 and NGFI-B mRNA in the prefrontal cortex Brodmann's areas 9 (BA 9) and BA 46 by in situ hybridization, and the protein levels in BA 9 by Western blotting, of patients with schizophrenia, major depression, and bipolar disorders, and non-psychiatric control subjects (n=15 per group). NGFI-B mRNA (P<0.05) and protein (P<0.01) were significantly lower in patients with schizophrenia (BA 9), and NGFI-B mRNA was lower in bipolar disorder (BA 9 and BA 46) than in the controls. In the deep cortical layers of BA 46, Nurr1 mRNA was significantly (P<0.05) lower in patients with bipolar disorder and schizophrenia than in the controls. Nurr1 protein in BA 9 was significantly lower in major depression (P<0.05) and lower at a trend level in schizophrenia (P=0.056) than in the controls. These data show a deficient prefrontal NGFI-B and Nurr1 expression in schizophrenia and bipolar disorder. Further study may elucidate if and how these deficiencies could be associated with abnormal dopaminergic functions seen in both illnesses.