title: Developmental Expression Patterns of KCC2 and Functionally Associated Molecules in the Human Brain.
abstract: Work on rodents demonstrated that steep upregulation of KCC2, a neuron-specific Cl-extruder of cation-chloride cotransporter (CCC) family, commences in supraspinal structures at around birth, leading to establishment of hyperpolarizing GABAergic responses. We describe spatiotemporal expression profiles of the entire CCC family in human brain. KCC2 mRNA was observed already at 10th postconceptional week (PCW) in amygdala, cerebellum, and thalamus. KCC2-immunoreactive (KCC2-ir) neurons were abundant in subplate at 18 PCW. By 25 PCW, numerous subplate and cortical plate neurons became KCC2-ir. The mRNA expression profiles of α- and β-isoforms of Na-K ATPase, which fuels cation-chloride cotransport, as well of tropomyosin receptor kinase B (TrkB), which promotes developmental upregulation of KCC2, were consistent with data from studies on rodents about their interactions with KCC2. Thus, in human brain, expression of KCC2 and its functionally associated proteins begins in early fetal period. Our work facilitates translation of results on CCC functions from animal studies to human and refutes the view that poor efficacy of anticonvulsants in the term human neonate is attributable to the lack of KCC2. We propose that perinatally low threshold for activation of Ca2+-dependent protease calpain renders neonates susceptible to downregulation of KCC2 by traumatic events, such as perinatal hypoxia ischemia.
authors.affiliation: Croatian Institute for Brain Research.
authors.forename: Goran
authors.initials: G
authors.lastname: Sedmak
authors.affiliation: Croatian Institute for Brain Research.
authors.forename: Nataša
authors.initials: N
authors.lastname: Jovanov-Milošević
authors.affiliation: Department of Biosciences and Neuroscience Center, University of Helsinki, Viikinkaari 1, Helsinki FI-00014, Finland.
authors.forename: Martin
authors.initials: M
authors.lastname: Puskarjov
authors.affiliation: Department of Pathology, Clinical Hospital Center Sisters of Mercy, University of Zagreb School of Medicine, Zagreb 10 000, Croatia.
authors.forename: Monika
authors.initials: M
authors.lastname: Ulamec
authors.affiliation: Department of Pathology, Clinical Hospital Center Sisters of Mercy, University of Zagreb School of Medicine, Zagreb 10 000, Croatia.
authors.forename: Božo
authors.initials: B
authors.lastname: Krušlin
authors.affiliation: Department of Biosciences and Neuroscience Center, University of Helsinki, Viikinkaari 1, Helsinki FI-00014, Finland mjudas@hiim.hr kai.kaila@helsinki.fi.
authors.forename: Kai
authors.initials: K
authors.lastname: Kaila
authors.affiliation: Croatian Institute for Brain Research mjudas@hiim.hr kai.kaila@helsinki.fi.
authors.forename: Miloš
authors.initials: M
authors.lastname: Judaš
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D002648:Child; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008562:Membrane Glycoproteins / Q000378:metabolism; D046228:Microarray Analysis; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D064506:Solute Carrier Family 12, Member 2 / Q000378:metabolism; D027981:Symporters / Q000378:metabolism*; D055815:Young Adult; D000096922:K Cl- Cotransporters
chemical_list: D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D020813:Receptor, trkB; D000254:Sodium-Potassium-Exchanging ATPase; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D000096922:K Cl- Cotransporters; C578877:SLC12A2 protein, human; C000606816:SLC12A5 protein, human; C119650:SLC12A6 protein, human; C000591259:tropomyosin-related kinase-B, human
keywords: KCC2; KCC3; NKCC1; Na-K ATPase; SLC12; TrkB; calpain; calpastatin; cation-chloride cotransporters; human brain