title: Deficits in transcriptional regulators of cortical parvalbumin neurons in schizophrenia.
abstract: OBJECTIVE
  In schizophrenia, alterations within the prefrontal cortical GABA system appear to be most prominent in neurons that contain parvalbumin or somatostatin but not calretinin. The transcription factors Lhx6 and Sox6 play critical roles in the specification, migration, and maturation of parvalbumin and somatostatin neurons, but not calretinin neurons, and continue to be strongly expressed in this cell type-specific manner in the prefrontal cortex of adult humans. The authors investigated whether Lhx6 and/or Sox6 mRNA levels are deficient in schizophrenia, which may contribute to cell type-specific disturbances in cortical parvalbumin and somatostatin neurons.
  
  
  METHODS
  The authors used quantitative PCR and in situ hybridization with film and grain counting analyses to quantify mRNA levels in postmortem samples of prefrontal cortex area 9 of 42 schizophrenia subjects and 42 comparison subjects who had no psychiatric diagnoses in life, as well as antipsychotic-exposed monkeys.
  
  
  RESULTS
  In schizophrenia subjects, the authors observed lower mRNA levels for Lhx6, parvalbumin, somatostatin, and glutamate decarboxylase (GAD67; the principal enzyme in GABA synthesis), but not Sox6 or calretinin. Cluster analysis revealed that a subset of schizophrenia subjects consistently showed the most severe deficits in the affected transcripts. Grain counting analyses revealed that some neurons that normally express Lhx6 were not detectable in schizophrenia subjects. Finally, lower Lhx6 mRNA levels were not attributable to psychotropic medications or illness chronicity.
  
  
  CONCLUSIONS
  These data suggest that in a subset of individuals with schizophrenia, Lhx6 deficits may contribute to a failure of some cortical parvalbumin and somatostatin neurons to successfully migrate or develop a detectable GABA-ergic phenotype.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, Pittsburgh, USA. volkdw@upmc.edu
authors.forename: David W
authors.initials: DW
authors.lastname: Volk
authors.forename: Takurou
authors.initials: T
authors.lastname: Matsubara
authors.forename: Siyu
authors.initials: S
authors.lastname: Li
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Sengupta
authors.forename: Danko
authors.initials: D
authors.lastname: Georgiev
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Minabe
authors.forename: Allan
authors.initials: A
authors.lastname: Sampson
authors.forename: Takanori
authors.initials: T
authors.lastname: Hashimoto
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D064032:Calbindin 2; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000172:deficiency* / Q000235:genetics; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism; D055755:SOXD Transcription Factors / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013004:Somatostatin / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
chemical_list: D014150:Antipsychotic Agents; C576764:CALB2 protein, human; D064032:Calbindin 2; C121947:LHX6 protein, human; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; C486270:SOX6 protein, human; D055755:SOXD Transcription Factors; D014157:Transcription Factors; D013004:Somatostatin