Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects.
OBJECTIVE
Abnormalities in prefrontal cortical gamma-aminobutyric acid (GABA) neurotransmission may contribute to cognitive dysfunction in schizophrenia. The density of chandelier neuron axon terminals (cartridges) immunoreactive for the GABA membrane transporter (GAT-1) has been reported to be reduced in the dorsolateral prefrontal cortex of schizophrenic subjects. Because cartridges regulate the output of pyramidal cells, this study analyzed the laminar distribution of GAT-1-immunoreactive cartridges to determine whether certain subpopulations of pyramidal cells are preferentially affected.


METHODS
Measurements were made of the density of GAT-1 -immunoreactive cartridges in layers 2-3a, 3b-4, and 6 of dorsolateral prefrontal cortex area 46 in 30 subjects with schizophrenia, each of whom was matched to one normal and one psychiatric comparison subject. GAT-1-immunoreactive cartridge density was also examined in monkeys chronically treated with haloperidol.


RESULTS
Relative to both comparison groups, the schizophrenic subjects had significantly lower GAT-1-immunoreactive cartridge density in layers 2-3a and 3b-4. The decrease was most common and most marked in layers 3b-4, where 80% of the schizophrenic subjects exhibited an average 50.1% decrease in cartridge density in comparison with the matched normal subjects. In contrast, GAT-1-immunoreactive cartridge density was unchanged in the haloperidol-treated monkeys.


CONCLUSIONS
These findings demonstrate that the density of GAT-1-immunoreactive cartridges is reduced in the majority of schizophrenic subjects and that this alteration may most prominently affect the function of pyramidal cells located in the middle cortical layers. This abnormality may reflect a number of underlying deficits, including a primary defect in dorsolateral prefrontal cortex circuitry or a secondary response to altered thalamic input to this region.
Pierri
J N
JN
Department of Psychiatry, University of Pittsburgh, PA 15213, USA.
Chaudry
A S
AS
Woo
T U
TU
Lewis
D A
DA
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001369:Axons / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D002352:Carrier Proteins / Q000032:analysis* / Q000378:metabolism / Q000502:physiology; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins / Q000032:analysis* / Q000378:metabolism / Q000502:physiology; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000032:analysis* / Q000378:metabolism / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D027361:Organic Anion Transporters; D017397:Prefrontal Cortex / Q000737:chemistry* / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000737:chemistry / Q000378:metabolism; D017966:Pyramidal Cells / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism
D014150:Antipsychotic Agents; D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D027361:Organic Anion Transporters; C493413:SLC6A1 protein, human; D006220:Haloperidol