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.
Xing
Guoqiang
G
Department of Psychiatry, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA. gxing@usuhs.mil
Zhang
Lei
L
Russell
Shani
S
Post
Robert
R
D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D016133:Polymerase Chain Reaction; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
D017931:DNA Primers; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C539882:NR4A2 protein, human; C539818:Nr4a1 protein, mouse; C539883:Nr4a2 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors