Characteristics of the cation cotransporter NKCC1 in human brain: alternate transcripts, expression in development, and potential relationships to brain function and schizophrenia.
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.
Clinical Brain Disorders Branch, Genes, Cognition, and Psychosis Program, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, Department of Psychiatry, Hiroshima City Hospital, Hiroshima City, Hiroshima Prefecture, 730-8518, Japan, Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland 21205, Neurodevelopmental and Neuropsychiatric Genetics Laboratory, Departments of Psychiatry and Cell and Developmental Biology, University of Colorado School of Medicine, Aurora, Colorado 80045, and Departments of Psychiatry, Neurology, Neuroscience and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Yukitaka
Y
Morita
Joseph H
JH
Callicott
Lauren R
LR
Testa
Michelle I
MI
Mighdoll
Dwight
D
Dickinson
Qiang
Q
Chen
Ran
R
Tao
Barbara K
BK
Lipska
Bhaskar
B
Kolachana
Amanda J
AJ
Law
Tianzhang
T
Ye
Richard E
RE
Straub
Daniel R
DR
Weinberger
Joel E
JE
Kleinman
Thomas M
TM
Hyde
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D003072:Cognition Disorders / Q000175:diagnosis / Q000209:etiology; D015331:Cohort Studies; D004274:DNA, Recombinant; D005260:Female; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010100:Oxygen / Q000097:blood; D011180:Postmortem Changes; D017397:Prefrontal Cortex / Q000098:blood supply / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000473:pathology*; D064506:Solute Carrier Family 12, Member 2 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D004274:DNA, Recombinant; D064506:Solute Carrier Family 12, Member 2; D010100:Oxygen
GABA; NKCC1; mRNA; neurotransmitter; schizophrenia; transcripts