RT Journal Article
SR Electronic
T1 Characteristics of the Cation Cotransporter NKCC1 in Human Brain: Alternate Transcripts, Expression in Development, and Potential Relationships to Brain Function and Schizophrenia
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4929
OP 4940
DO 10.1523/JNEUROSCI.1423-13.2014
VO 34
IS 14
A1 Yukitaka Morita
A1 Joseph H. Callicott
A1 Lauren R. Testa
A1 Michelle I. Mighdoll
A1 Dwight Dickinson
A1 Qiang Chen
A1 Ran Tao
A1 Barbara K. Lipska
A1 Bhaskar Kolachana
A1 Amanda J. Law
A1 Tianzhang Ye
A1 Richard E. Straub
A1 Daniel R. Weinberger
A1 Joel E. Kleinman
A1 Thomas M. Hyde
YR 2014
UL http://www.jneurosci.org/content/34/14/4929.abstract
AB 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.