27 April 2012. A splice variant of the chloride transporter KCC2 is increased in dorsolateral prefrontal cortex (DLPFC) tissue of schizophrenia subjects, but lower in subjects with major depressive disorder, reports Thomas Hyde of the National Institute of Mental Health in Bethesda, Maryland, in the April 11 issue of The Journal of Neuroscience. Hyde and colleagues also demonstrate that another splice variant in KCC2 is associated with a schizophrenia risk variant in the gene that encodes the GABA-synthesizing enzyme GAD67. This work was first reported by SRF in Bart Rutten’s 2011 International Congress on Schizophrenia Research meeting report (see SRF related news story).
Levels of KCC2 (aka SLC12A5), which removes chloride from the cell, rise in early in postnatal development, resulting in an excitatory-to-inhibitory switch in GABA neurotransmission (Ben-Ari, 2002). In the past several years, KCC2 has been implicated in schizophrenia, with reports of lower mRNA levels in the hippocampus but not the DLPFC (Hyde et al., 2011), and increased expression of chloride transporter-regulating kinases in the DLPFC (Arion and Lewis, 2010). In addition, the gene for KCC2 resides in a chromosomal region that shows linkage with schizophrenia (Freedman et al., 2001).
Since full-length KCC2 is known to undergo alternative splicing, in the current study first author Ran Tao and colleagues set out to identify its alternative transcripts, finding 11 novel ones. The authors then examined the mRNA expression patterns of four of the truncated variants across development, demonstrating that three increased between fetal life and adulthood, while levels of the fourth dropped over a similar period. In a cohort of psychiatric subjects, one transcript (EXON6B) was significantly increased in schizophrenia subjects, but decreased in subjects with major depressive disorder. No change was observed in bipolar disorder subjects. The other three transcripts showed no significant effect in any of the illnesses in the full cohort, although one (AK098371) was significantly reduced in schizophrenia when compared to control subjects alone (and not to other psychiatric illnesses). This same splice variant was also associated with a putative schizophrenia risk single nucleotide polymorphism in GAD1, the gene for GAD67, in a combined cohort of schizophrenia and control subjects, with the risk allele predicting lower AK098371 expression.
The finding of an increasing pattern of AK098371 expression across the lifespan, coupled with lower levels in schizophrenia, is suggestive of an immature pattern of expression in the illness. Opposite alterations of EXON6B in schizophrenia and major depressive disorder point to disparate roles of this transcript in the pathology of the two illnesses. Interestingly, full-length KCC2 plays another role in the nervous system besides ion transport: regulation of dendritic spine maturation (Li et al., 2007). Since neither EXON6B nor AK098371 contain the protein domain required for ion transport, they too may be involved in the control of dendritic spine morphology.—Allison A. Curley.
Tao R, Li C, Newburn EN, Ye T, Lipska BK, Herman MM, Weinberger DR, Kleinman JE, Hyde TM. Transcript-Specific Associations of SLC12A5 (KCC2) in Human Prefrontal Cortex with Development, Schizophrenia, and Affective Disorders. J Neurosci . 2012 Apr 11 ; 32(15):5216-22. Abstract.