Characteristics of the Cation Cotransporter NKCC1 in Human Brain: Alternate Transcripts, Expression in Development, and Potential Relationships to Brain Function and Schizophrenia
| Autor: | Daniel R. Weinberger, Joseph H. Callicott, Amanda J. Law, Dwight Dickinson, Lauren R. Testa, Joel E. Kleinman, Barbara K. Lipska, Michelle I. Mighdoll, Tianzhang Ye, Yukitaka Morita, Ran Tao, Richard E. Straub, Bhaskar Kolachana, Qiang Chen, Thomas M. Hyde |
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| Rok vydání: | 2014 |
| Předmět: |
Adult
Male medicine.medical_specialty Adolescent Genotype DNA Recombinant Prefrontal Cortex Biology Inhibitory postsynaptic potential Cohort Studies Young Adult chemistry.chemical_compound Fetus Internal medicine medicine Humans Solute Carrier Family 12 Member 2 Allele Child Neurotransmitter Aged Psychiatric Status Rating Scales Working memory General Neuroscience Infant Newborn Gene Expression Regulation Developmental Infant Articles Human brain Middle Aged Phenotype Oxygen Minor allele frequency HEK293 Cells medicine.anatomical_structure Endocrinology chemistry Child Preschool Postmortem Changes Mutation Schizophrenia Excitatory postsynaptic potential Female Cognition Disorders Neuroscience |
| Zdroj: | The Journal of Neuroscience. 34:4929-4940 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | 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 org(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. |
| Databáze: | OpenAIRE |
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