Characteristics of the cation cotransporter NKCC1 in human brain: Alternate transcripts, expression in development, and potential relationships to brain function and Schizophrenia

Yukitaka Morita, Joseph H. Callicott, Lauren R. Testa, Michelle I. Mighdoll, Dwight Dickinson, Qiang Chen, Ran Tao, Barbara K. Lipska, Bhaskar Kolachana, Amanda J. Law, Tianzhang Ye, Richard E. Straub, Daniel R. Weinberger, Joel E. Kleinman, Thomas M. Hyde

Research output: Contribution to journalArticle

Abstract

Early in development, GABA, an inhibitory neurotransmitter in adults, is excitatory. NKCC1 (SLC12A2) encodes one of two cation chloride cotransporters mediating the conversion of GABA from excitatory to inhibitory. Using 3′ and 5′ RACE and PCR, we verified previously characterized alternative transcripts of NKCC1a (1-27) and NKCC1b (1-27(Δ21)), identified new NKCC1 transcripts, and explored their expression patterns during human prefrontal cortical development. A novel ultra-short transcript (1-2a) was expressed preferentially in the fetus. Expression of NKCC1b and 1-2a were decreased in schizophrenia compared with controls (NKCC1b: 0.8-fold decrease, p = 0.013; 1-2a: 0.8-fold decrease, p = 0.006). Furthermore, the expression of NKCC1b was associated with NKCC1 polymorphism rs3087889. The minor allele at rs3087889, associated with reduced NKCC1b expression (homozygous for major allele: N = 37; homozygous for minor allele: N = 15; 1.5-fold decrease; p < 0.01), was also associated with a modest increase in schizophrenia risk in a case-control sample (controls: N = 435; cases: N = 397, OR = 1.5). This same allele was then found associated with cognitive (n = 369) and fMRI (n = 313) intermediate phenotypes associated with schizophrenia-working memory (Cohen's d = 0.35), global cognition or g (d = 0.18), and prefrontal inefficiency (d = 0.36) as measured by BOLD fMRI during a working memory task. Together, these preclinical and clinical results suggest that variation in NKCC1 may increase risk for schizophrenia via alterations of mRNA expression at the molecular level and impairment of optimal prefrontal function at the macro or systems level.

Original languageEnglish (US)
Pages (from-to)4929-4940
Number of pages12
JournalJournal of Neuroscience
Volume34
Issue number14
DOIs
StatePublished - 2014

Keywords

  • GABA
  • NKCC1
  • Neurotransmitter
  • Schizophrenia
  • Transcripts
  • mRNA

ASJC Scopus subject areas

  • Neuroscience(all)

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