Schizophrenia Research Forum - A Catalyst for Creative Thinking
Home Profile Membership/Get Newsletter Log In Contact Us
 For Patients & Families
What's New
Recent Updates
SRF Papers
Current Papers
Search All Papers
Search Comments
News
Research News
Conference News
Plain English
Forums
Current Hypotheses
Idea Lab
Online Discussions
Virtual Conferences
Interviews
Resources
What We Know
SchizophreniaGene
Animal Models
Drugs in Trials
Research Tools
Grants
Jobs
Conferences
Journals
Community Calendar
General Information
Community
Member Directory
Researcher Profiles
Institutes and Labs
About the Site
Mission
History
SRF Team
Advisory Board
Support Us
How to Cite
Fan (E)Mail
The Schizophrenia Research Forum web site is sponsored by the Brain and Behavior Research Foundation and was created with funding from the U.S. National Institute of Mental Health.
Research News
back to News Search
News Brief: Altered KCC2 Splice Variant Levels in Schizophrenia

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.

Reference:
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.

 
Comments on Related Papers
Related Paper: Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia.

Comment by:  Patricio O'Donnell, SRF Advisor
Submitted 10 August 2011 Posted 10 August 2011
  I recommend this paper

Very interesting report of developmental (pre- and postnatal) changes in several markers of GABA function in the prefrontal cortex of a large cohort of normal humans. The observation of developmental switches in the expression of genes (GAD25 to GAD67 and NKCC1 to KCC2) may be of importance in the peri-adolescent acquisition of abnormal interneuron function that has been proposed in schizophrenia.

View all comments by Patricio O'Donnell

Submit a Comment on this News Article
Make a comment on this news article. 

If you already are a member, please login.
Not sure if you are a member? Search our member database.

*First Name  
*Last Name  
Affiliation  
Country or Territory  
*Login Email Address  
*Confirm Email Address  
*Password  
*Confirm Password  
Remember my Login and Password?  
Get SRF newsletter with recent commentary?  
 
Enter the code as it is shown below:
This code helps prevent automated registrations.

I recommend the Primary Papers

Please note: A member needs to be both registered and logged in to submit a comment.

Comment:

(If coauthors exist for this comment, please enter their names and email addresses at the end of the comment.)

References:


SRF News
SRF Comments
Text Size
Reset Text Size
Email this pageEmail this page

Share/Bookmark
Copyright © 2005- 2014 Schizophrenia Research Forum Privacy Policy Disclaimer Disclosure Copyright