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The European Journal of Psychiatry

Print version ISSN 0213-6163

Abstract

HEIDE, Juliane; VANDENBERG, Jamie I.  and  SHANNON WEICKERT, Cynthia. Expression of KCNH2-3.1 mRNA is increased in small neurons in the dorsolateral prefrontal cortex in patients with schizophrenia. Eur. J. Psychiat. [online]. 2015, vol.29, n.2, pp.85-103. ISSN 0213-6163.  http://dx.doi.org/10.4321/S0213-61632015000200001.

Background and Objectives: Abnormalities in neuronal firing, controlled and organised by a series of voltage-gated ion channels, may contribute to the pathogenesis of schizophrenia. KCNH2, encoding the voltage-gated potassium channel Kv11.1, has been identified as a potential risk gene for schizophrenia. Single nucleotide polymorphisms (SNPs) in the second intron promote the expression of a brain-specific isoform, KCNH2-3.1, which exhibits altered gating kinetics and results in less adaptation of firing rate in response to prolonged stimulation. To determine the pathophysiological consequence of these altered gating properties, we need to know in which cells KCNH2-3.1 is expressed and how this is affected by genotype and/or diagnosis. Methods: We performed SNP analysis and in-situ hybridization on brain tissue from 37 healthy controls and schizophrenia (n = 30)/schizoaffective (n = 7) patients to investigate expression levels and cellular distribution of KCNH2-3.1 mRNA in the dorsolateral prefrontal cortex (DLPFC). Results: KCNH2-3.1 mRNA is expressed in all six layers of the DLPFC. It is expressed in both pyramidal and interneuron-like cells, with significantly higher expression in small neurons in layer III and IV in schizophrenia patients compared to controls. Schizophrenia/schizoaffective patients who carry risk alleles at rs11763131 and/or rs3807373 show significantly higher expression in layer IV compared to schizophrenia/schizoaffective patients who are non-risk allele carriers. Conclusions: We have anatomically localized an increase in KCNH2-3.1 to putative interneurons in schizophrenia/schizoaffective. Our results demonstrate that the risk alleles are likely to be preferentially associated with higher KCNH2-3.1 mRNA expression, which would be expected to result in increased spike frequency and firing in layer IV interneurons.

Keywords : Schizophrenia; SNPs; KCNH2-3.1; DLPFC; Interneurons.

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