GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons.
OBJECTIVE
Within the prefrontal cortex of schizophrenic subjects, alterations in markers of gamma-aminobutyric acid (GABA) neurotransmission, including decreased immunoreactivity for the GABA membrane transporter GAT-1, may be most prominent in a subset of inhibitory neurons. In the present study, the authors sought to determine whether the alterations in GAT-1 protein could be attributed to a reduction in GAT-1 mRNA expression.


METHODS
Tissue sections containing prefrontal cortex area 9 from 10 matched pairs of schizophrenic and comparison subjects were processed for in situ hybridization histochemistry with (35)S-oligonucleotide probes for GAT-1 mRNA.


RESULTS
In the schizophrenic subjects, the relative density of labeled neurons was 21%-33% lower in layers 1-5 of the prefrontal cortex but was unchanged in layer 6. In contrast, cellular levels of GAT-1 mRNA expression, as reflected in grain density per labeled neuron, did not differ by more than 11% between subject groups in any layer. These findings indicate that GAT-1 mRNA expression is relatively unaltered in the majority of prefrontal cortex GABA neurons in schizophrenic subjects but is reduced below a detectable level in a subset of GABA neurons. Furthermore, the magnitude and laminar pattern of these results were strikingly similar to those found in a previous study of mRNA expression for the synthesizing enzyme of GABA, glutamic acid decarboxylase(67), in the same subjects.


CONCLUSIONS
Both GABA synthesis and reuptake appear to be altered at the level of gene expression in a subset of GABA neurons, and the resulting changes in GABA neurotransmission may contribute to prefrontal cortex dysfunction in schizophrenia.
Volk
D
D
Department of Neuroscience, University of Pittsburgh, PA 15213, USA.
Austin
M
M
Pierri
J
J
Sampson
A
A
Lewis
D
D
D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins; D015870:Gene Expression; D006220:Haloperidol / Q000493:pharmacokinetics; D006801:Humans; D017403:In Situ Hybridization; D008252:Macaca fascicularis; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D015345:Oligonucleotide Probes; D027361:Organic Anion Transporters; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D012559:Schizophrenia / Q000175:diagnosis* / Q000378:metabolism; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D015345:Oligonucleotide Probes; D027361:Organic Anion Transporters; D012333:RNA, Messenger; C493413:SLC6A1 protein, human; D005680:gamma-Aminobutyric Acid; D006220:Haloperidol