title: Expression of GABA signaling molecules KCC2, NKCC1, and GAD1 in cortical development and schizophrenia.
abstract: GABA signaling molecules are critical for both human brain development and the pathophysiology of schizophrenia. We examined the expression of transcripts derived from three genes related to GABA signaling [GAD1 (GAD67 and GAD25), SLC12A2 (NKCC1), and SLC12A5 (KCC2)] in the prefrontal cortex (PFC) and hippocampal formation of a large cohort of nonpsychiatric control human brains (n = 240) across the lifespan (from fetal week 14 to 80 years) and in patients with schizophrenia (n = 30-31), using quantitative RT-PCR. We also examined whether a schizophrenia risk-associated promoter SNP in GAD1 (rs3749034) is related to expression of these transcripts. Our studies revealed that development and maturation of both the PFC and hippocampal formation are characterized by progressive switches in expression from GAD25 to GAD67 and from NKCC1 to KCC2. Previous studies have demonstrated that the former leads to GABA synthesis, and the latter leads to switching from excitatory to inhibitory neurotransmission. In the hippocampal formation, GAD25/GAD67 and NKCC1/KCC2 ratios are increased in patients with schizophrenia, reflecting a potentially immature GABA physiology. Remarkably, GAD25/GAD67 and NKCC1/KCC2 expression ratios are associated with rs3749034 genotype, with risk alleles again predicting a relatively less mature pattern. These findings suggest that abnormalities in GABA signaling critical to brain development contribute to genetic risk for schizophrenia.
authors.affiliation: Section on Neuropathology, Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA. hydet@mail.nih.gov
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Hyde
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Lipska
authors.forename: Towhid
authors.initials: T
authors.lastname: Ali
authors.forename: Shiny V
authors.initials: SV
authors.lastname: Mathew
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Law
authors.forename: Ochuko E
authors.initials: OE
authors.lastname: Metitiri
authors.forename: Richard E
authors.initials: RE
authors.lastname: Straub
authors.forename: Tianzhang
authors.initials: T
authors.lastname: Ye
authors.forename: Carlo
authors.initials: C
authors.lastname: Colantuoni
authors.forename: Mary M
authors.initials: MM
authors.lastname: Herman
authors.forename: Llewellyn B
authors.initials: LB
authors.lastname: Bigelow
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Joel E
authors.initials: JE
authors.lastname: Kleinman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000196:embryology* / Q000254:growth & development* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000235:genetics / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D014150:Antipsychotic Agents; D005968:Glutamate Decarboxylase; D012333:RNA, Messenger; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C578877:SLC12A2 protein, human; C578879:Slc12a2 protein, rat; C402565:glutamate decarboxylase 1