title: KCC2-mediated regulation of respiration-related rhythmic activity during postnatal development in mouse medulla oblongata.
abstract: GABA acts as inhibitory neurotransmitter in the adult central nervous system but as excitatory neurotransmitter during early postnatal development. This shift in GABA's action from excitation to inhibition is caused by a decrease in intracellular chloride concentration ([Cl(-)]i), which in turn is caused by changes in the relative expression levels of the K(+)-Cl(-) co-transporter (KCC2) and the Na(+), K(+)-2Cl(-) co-transporter (NKCC1) proteins. Previous studies have used slices containing the medullary pre-Bötzinger complex (pre-BötC) to record respiration-related rhythmic activity (RRA) from the hypoglossal nucleus (12 N). The role of GABAergic transmission in the regulation of medullary RRA neonatally, however, is yet to be determined. Here, we examined how GABA and chloride co-transporters contribute to RRA during development in the 12 N where inspiratory neurons reside. We recorded extracellular RRA in medullary slices obtained from postnatal day (P) 0-7 mice. RRA was induced by soaking slices in artificial cerebrospinal fluid (aCSF) containing 8mM-K(+). Application of GABA significantly increased the frequency of RRA after P3, whereas application of a KCC2 blocker (R (+)-[(2-n-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-indenyl-5-yl)oxy]acetic acid (DIOA)) significantly decreased the frequency of RRA after P1. In addition, dense KCC2 immunolabeling was seen in the superior longitudinalis (SL) of the 12 N, which is responsible for retraction of the tongue, from P0 and P7. These results indicate that GABA administration can increase RRA frequency during the first week following birth. This in turn suggests that decreasing [Cl(-)]i levels caused by increasing KCC2 levels in the 12 N could play important roles in regulating the frequency of RRA during development.
authors.affiliation: Department of Molecular Anatomy, School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. Electronic address: okabe@med.u-ryukyu.ac.jp.
authors.forename: Akihito
authors.initials: A
authors.lastname: Okabe
authors.affiliation: Department of Molecular Anatomy, School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
authors.forename: Chigusa
authors.initials: C
authors.lastname: Shimizu-Okabe
authors.affiliation: Division of Physiome, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Arata
authors.affiliation: Department of Neurophysiology, Kagawa School of Pharmaceutical Science, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2101, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Konishi
authors.affiliation: Department of Neurophysiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Fukuda
authors.affiliation: Department of Molecular Anatomy, School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
authors.forename: Chitoshi
authors.initials: C
authors.lastname: Takayama
mesh_terms: D000818:Animals; D008526:Medulla Oblongata / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012119:Respiration / Q000187:drug effects; D064506:Solute Carrier Family 12, Member 2 / Q000502:physiology; D027981:Symporters / Q000378:metabolism / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000502:physiology*; D000096922:K Cl- Cotransporters
chemical_list: D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C578878:Slc12a2 protein, mouse
keywords: K(+)–Cl(−) co-transporter 2 (KCC2); Na(+), K(+)–2Cl(−) co-transporter 1 (NKCC1); γ-Amino butyric acid (GABA)