Feature Finding Title
Feature Finding Figure
Disturbances in markers of cortical GABA neurotransmission are a common finding in schizophrenia. The nature of GABA 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 two 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, 3 and 4. We used real-time qPCR to compare the levels of NKCC1, KCC2, OXSR1, STK39, WNK1, WNK3 and WNK4 transcripts in prefrontal cortex area 9 from 42 subjects with schizophrenia and 42 matched normal comparison subjects, and from 18 macaque monkeys chronically exposed to haloperidol, olanzapine, or sham. OXSR1 and WNK3 transcripts were substantially over-expressed in 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. As illustrated in panel A, in normal adult neurons, intracellular chloride concentration is low due to low levels of NKCC1 and high levels of KCC2. The binding of GABA to GABA-A receptors triggers chloride entry (chloride flow is represented by green arrows) and hyperpolarization. In schizophrenia (panel B) increased OXSR1 and WNK3-1 kinase levels lead to increased phosphorylation (blue P) and consequently increased NKCC1 activity and decreased KCC2 activity, producing a greater intracellular chloride concentration. Thus, when GABA-A receptors are activated chloride influx is reduced (or perhaps reversed) and the nature of GABA neurotransmission is altered.
Arion D and Lewis DA: Altered expression of regulators of the cortical choloride transporters NKCC1 and KCC2 in schizophrenia. Arch Gen Psychiatry, 68:21-31, 2011.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
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