Lamina-specific alterations in cortical GABA(A) receptor subunit expression in schizophrenia.
Dysfunction of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia is associated with lamina-specific alterations in particular subpopulations of interneurons. In pyramidal cells, postsynaptic γ-aminobutyric acid (GABA(A)) receptors containing different α subunits are inserted preferentially in distinct subcellular locations targeted by inputs from specific interneuron subpopulations. We used in situ hybridization to quantify the laminar expression of α1, α2, α3, and α5 subunit, and of β1-3 subunit, mRNAs in the DLFPC of schizophrenia, and matched normal comparison subjects. In subjects with schizophrenia, mean GABA(A) α1 mRNA expression was 17% lower in layers 3 and 4, α2 expression was 14% higher in layer 2, α5 expression was 15% lower in layer 4, and α3 expression did not differ relative to comparison subjects. The mRNA expression of β2, which preferentially assembles with α1 subunits, was also 20% lower in layers 3 and 4, whereas β1 and β3 mRNA levels were not altered in schizophrenia. These expression differences were not attributable to medication effects or other potential confounds. These findings suggest that GABA neurotransmission in the DLPFC is altered at the postsynaptic level in a receptor subunit- and layer-specific manner in subjects with schizophrenia and support the hypothesis that GABA neurotransmission in this illness is predominantly impaired in certain cortical microcircuits.
Beneyto
Monica
M
Department of Psychiatry, University of Pittsburgh, W1656 Biomedical Science Tower, 3811 O'Hara Street, Pittsburgh, PA 15213, USA. beneytom@upmc.edu
Abbott
Andrew
A
Hashimoto
Takanori
T
Lewis
David A
DA
D000328:Adult; D000368:Aged; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000235:genetics
C546240:GABRA1 protein, human; C484841:GABRA2 protein, human; C546257:GABRA3 protein, human; C527986:GABRA5 protein, human; C546264:GABRB1 protein, human; C495710:GABRB2 protein, human; C546273:GABRB3 protein, human; D012333:RNA, Messenger; D011963:Receptors, GABA-A