title: Altered markers of tonic inhibition in the dorsolateral prefrontal cortex of subjects with schizophrenia.
abstract: OBJECTIVE
  Cognitive impairments in schizophrenia are associated with lower expression of markers of gamma-aminobutyric acid (GABA) synthesis in the prefrontal cortex. The effects of GABA are mediated by GABA(A) receptors that mediate either phasic or tonic inhibition. The authors assessed the expression of GABA(A) receptor alpha4 and delta subunits, which coassemble to form receptors mediating tonic inhibition, in schizophrenia.
  
  
  METHODS
  The authors used in situ hybridization to quantify expression patterns of GABA(A) receptor alpha4 and delta subunits in prefrontal cortex from 23 matched pairs of schizophrenia and comparison subjects.
  
  
  RESULTS
  Levels of delta mRNA were significantly lower in schizophrenia subjects regardless of medication use, whereas alpha4 mRNA levels were lower only in subjects with schizophrenia receiving certain medications at the time of death. To understand the nature of this unexpected dissociation between alpha4 and delta subunit expression in schizophrenia, the authors used similar methods to quantify alpha4 and delta mRNA levels in multiple animal models. During postnatal development of monkey prefrontal cortex, levels of alpha4 mRNA decreased, whereas delta mRNA levels increased. In addition, delta mRNA levels, but not alpha4 mRNA levels, were lower in the medial frontal cortex of mice with a genetic deletion of the GABA(A) receptor alpha1 subunit, and neither delta nor alpha4 mRNA levels were altered in rodent models of altered excitatory neurotransmission.
  
  
  CONCLUSIONS
  Since GABA(A) receptor alpha1 subunits also have lower mRNA levels in schizophrenia, show increased expression with age in monkey prefrontal cortex, and can coassemble with delta subunits to form functional GABA(A) receptors, lower delta mRNA levels in schizophrenia might reflect a reduced number of alpha(1)beta(x)delta GABA(A) receptors that could contribute to deficient tonic inhibition and prefrontal cortical dysfunction in schizophrenia.
authors.affiliation: Department of Psychiatry, University of Pittsburgh, 3811 O'Hara St., W1651 BST, Pittsburgh, PA 15213, USA.
authors.forename: Jaime G
authors.initials: JG
authors.lastname: Maldonado-Avilés
authors.forename: Allison A
authors.initials: AA
authors.lastname: Curley
authors.forename: Takanori
authors.initials: T
authors.lastname: Hashimoto
authors.forename: A Leslie
authors.initials: AL
authors.lastname: Morrow
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Ramsey
authors.forename: Patricio
authors.initials: P
authors.lastname: O'Donnell
authors.forename: David W
authors.initials: DW
authors.lastname: Volk
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009433:Neural Inhibition / Q000235:genetics*; D017397:Prefrontal Cortex / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics*; D051381:Rats; D011963:Receptors, GABA-A / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D011963:Receptors, GABA-A