Altered expression of regulators of the cortical chloride transporters NKCC1 and KCC2 in schizophrenia.
BACKGROUND
Disturbances in markers of cortical γ-aminobutyric acid neurotransmission are a common finding in schizophrenia. The nature of γ-aminobutyric acid neurotransmission (hyperpolarizing or depolarizing) depends on the local intracellular chloride concentration. In the central nervous system, the intracellular chloride level is determined by the activity of 2 cation-chloride transporters, NKCC1 and KCC2. The activities of these transporters are in turn regulated by a network of serine-threonine kinases that includes OXSR1, STK39, and the WNK kinases WNK1, WNK3, and WNK4.


OBJECTIVE
To compare the levels of NKCC1, KCC2, OXSR1, STK39, WNK1, WNK3, and WNK4 transcripts in prefrontal cortex area 9 between subjects with schizophrenia and healthy comparison subjects.


METHODS
Real-time quantitative polymerase chain reaction technique was used to measure transcript levels in the prefrontal cortex.


METHODS
Human brain specimens were obtained from autopsies conducted at the Allegheny County Medical Examiner's Office, Pittsburgh, Pennsylvania.


METHODS
Postmortem brain specimens from 42 subjects with schizophrenia and 42 matched healthy comparison subjects. Brain specimens from 18 macaque monkeys exposed to haloperidol, olanzapine, or sham long-term.


METHODS
Relative expression levels for NKCC1, KCC2, OXSR1, STK39, WNK1, WNK3, and WNK4 transcripts compared with the mean expression level of 3 housekeeping transcripts.


RESULTS
OXSR1 and WNK3 transcripts were substantially overexpressed in subjects with schizophrenia relative to comparison subjects. In contrast, NKCC1, KCC2, STK39, WNK1, and WNK4 transcript levels did not differ between subject groups. OXSR1 and WNK3 transcript expression levels were not changed in antipsychotic-exposed monkeys and were not affected by potential confounding factors in the subjects with schizophrenia.


CONCLUSIONS
In schizophrenia, increased expression levels, and possibly increased kinase activities, of OXSR1 and WNK3 may shift the balance of chloride transport by NKCC1 and KCC2 and alter the nature of γ-aminobutyric acid neurotransmission in the prefrontal cortex.
Arion
Dominique
D
Department of Psychiatry, University of Pittsburgh, PA 15213, USA.
Lewis
David A
DA
D000328:Adult; D001344:Autopsy; D016022:Case-Control Studies; D002712:Chlorides / Q000378:metabolism; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D017136:Ion Transport / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D017397:Prefrontal Cortex / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism*; D064466:Solute Carrier Family 12, Member 1; D064506:Solute Carrier Family 12, Member 2; D015854:Up-Regulation / Q000235:genetics; D000076204:WNK Lysine-Deficient Protein Kinase 1
D002712:Chlorides; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; C578714:SLC12A1 protein, human; C578877:SLC12A2 protein, human; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1; D064506:Solute Carrier Family 12, Member 2; C118135:OXSR1 protein, human; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; C488586:WNK3 protein, human; C433806:WNK4 protein, human
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