Dataset Information

Characteristics of the cation cotransporter NKCC1 in human brain: alternate transcripts, expression in development, and potential relationships to brain function and schizophrenia.

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(?21)), 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.

SUBMITTER: Morita Y

PROVIDER: S-EPMC3972720 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Characteristics of the cation cotransporter NKCC1 in human brain: alternate transcripts, expression in development, and potential relationships to brain function and schizophrenia.

Morita Yukitaka Y Callicott Joseph H JH Testa Lauren R LR Mighdoll Michelle I MI Dickinson Dwight D Chen Qiang Q Tao Ran R Lipska Barbara K BK Kolachana Bhaskar B Law Amanda J AJ Ye Tianzhang T Straub Richard E RE Weinberger Daniel R DR Kleinman Joel E JE Hyde Thomas M TM

The Journal of neuroscience : the official journal of the Society for Neuroscience 20140401 14

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- ...[more]

PMID: 24695712

Similar Datasets

Project description:PURPOSE: To characterize the expression patterns of the Na+-K+-Cl(-) cotransporter (NKCC) 1 and NKCC2, and the Na+-Cl(-) cotransporter (NCC) in the rat lens and to determine if they play a role in regulating lens volume and transparency. METHODS: RT-PCR was performed on RNA extracted from fiber cells to identify sodium dependent cotransporters expressed in the rat lens. Western blotting and immunohistochemistry, using NKCC1, NKCC2, and NCC antibodies, were used to verify expression at the protein level and to localize transporter expression. Organ cultured rat lenses were incubated in Artificial Aqueous Humor (AAH) of varying osmolarities or isotonic AAH that contained either the NKCC specific inhibitor bumetanide, or the NCC specific inhibitor thiazide for up to 18 h. Lens transparency was monitored with dark field microscopy, while tissue morphology and antibody labeling patterns were recorded using a confocal microscope. RESULTS: Molecular experiments showed that NKCC1 and NCC were expressed in the lens at both the transcript and protein levels, but NKCC2 was not. Immunohistochemistry showed that both NKCC1 and NCC were expressed in the lens cortex, but NCC expression was also found in the lens core. In the lens cortex the majority of labeling for both transporters was cytoplasmic in nature, while in the lens core, NCC labeling was associated with the membrane. Exposure of lenses to either hypotonic or hypertonic AAH had no noticeable effects on the predominantly cytoplasmic location of either transporter in the lens cortex. Incubation of lenses in isotonic AAH plus the NKCC inhibitor bumetanide for 18 h induced a cortical opacity that was initiated by a shrinkage of peripheral fiber cells and the dilation of the extracellular space between fiber cells in a deeper zone located some approximately 150 microm in from the capsule. In contrast, lenses incubated in isotonic AAH and the NCC inhibitor thiazide maintained both their transparency and their regular fiber cell morphology. CONCLUSIONS: We have confirmed the expression of NKCC1 in the rat lens and report for the first time the expression of NCC in lens fiber cells. The expression patterns of the two transporters and the differential effects of their specific inhibitors on fiber cell morphology indicate that these transporters play distinct roles in the lens. NKCC1 appears to mediate ion influx in the lens cortex while NCC may play a role in the lens nucleus.

Dataset Information

Characteristics of the cation cotransporter NKCC1 in human brain: alternate transcripts, expression in development, and potential relationships to brain function and schizophrenia.

Publications

Characteristics of the cation cotransporter NKCC1 in human brain: alternate transcripts, expression in development, and potential relationships to brain function and schizophrenia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets