Cortical inhibitory neuron disturbances in schizophrenia: role of the ontogenetic transcription factor Lhx6.
Disturbances in parvalbumin- and somatostatin-containing neurons, including deficits in the gamma-aminobutyric acid (GABA)-synthesizing enzyme GAD67 in the prefrontal cortex (PFC) in schizophrenia, may be related to disrupted pre- and/or postnatal development. Deficits in the transcription factor Lhx6, which regulates parvalbumin and somatostatin neuron development, are associated with GAD67 deficits in schizophrenia. Therefore, we investigated the potential pre- and postnatal roles of Lhx6 in GABA-related disturbances using qPCR and/or in situ hybridization to quantify PFC levels of (1) Lhx6 mRNA in a new cohort of schizophrenia subjects; (2) Lhx6 mRNA in monkeys across postnatal development; (3) GABA-related mRNAs in Lhx6 heterozygous (Lhx6+/−) mice, which model Lhx6 deficits in schizophrenia; and (4) Lhx6 mRNA in GAD67+/− mice, which model GAD67 deficits in schizophrenia. Lhx6 mRNA levels were lower (−15%) in schizophrenia and correlated with lower GAD67 mRNA levels. In addition, Lhx6 mRNA levels declined 24% from the perinatal to prepubertal periods then stabilized in monkeys. Finally, GAD67, parvalbumin, and somatostatin mRNAs were not altered in Lhx6+/− mice, and Lhx6 mRNA was not altered in GAD67+/− mice. These data suggest that PFC Lhx6 and GAD67 mRNA deficits are common components of GABA neuron pathology in schizophrenia. An excessive early postnatal decline in Lhx6 mRNA might contribute to Lhx6 mRNA deficits in schizophrenia. However, a partial loss of Lhx6 is not sufficient in isolation to produce deficits in GAD67 mRNA and vice versa, suggesting that the concurrence of Lhx6 and GAD67 mRNA deficits in schizophrenia may instead be the consequence of a common upstream factor.
David W
DW
Volk
Jessica R
JR
Edelson
David A
DA
Lewis
D000328:Adult; D000367:Age Factors; D000368:Aged; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010320:Parvalbumins / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism*; D013004:Somatostatin / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
C121947:LHX6 protein, human; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D012333:RNA, Messenger; D014157:Transcription Factors; D013004:Somatostatin; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1