title: The Timing of the Excitatory-to-Inhibitory GABA Switch Is Regulated by the Oxytocin Receptor via KCC2.
abstract: Oxytocin and its receptor (Oxtr) play a crucial role in the postnatal transition of neuronal GABA neurotransmission from excitatory to inhibitory, a developmental process known as the GABA switch. Using hippocampal neurons from Oxtr-null mice, we show that (1) Oxtr is necessary for the correct timing of the GABA switch by upregulating activity of the chloride cotransporter KCC2, (2) Oxtr, in a very early and narrow time window, directly modulates the functional activity of KCC2 by promoting its phosphorylation and insertion/stabilization at the neuronal surface, and (3) in the absence of Oxtr, electrophysiological alterations are recorded in mature neurons, a finding consistent with a reduced level of KCC2 and increased susceptibility to seizures observed in adult Oxtr-null mice. These data identify KCC2 as a key target of oxytocin in postnatal events that may be linked to pathogenesis of neurodevelopmental disorders.
authors.affiliation: Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Milan 20129, Italy; Department of Biotechnology and Translational Medicine, University of Milan, Milan 20129, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Leonzino
authors.affiliation: Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Milan 20129, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Busnelli
authors.affiliation: Department of Biotechnology and Translational Medicine, University of Milan, Milan 20129, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Antonucci
authors.affiliation: Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Milan 20129, Italy; Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan 20089, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Verderio
authors.affiliation: Department of Bioscience, University of Milan, Milan 20133, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Mazzanti
authors.affiliation: Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Milan 20129, Italy; Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan 20089, Italy. Electronic address: b.chini@in.cnr.it.
authors.forename: Bice
authors.initials: B
authors.lastname: Chini
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials; D059330:GABAergic Neurons / Q000378:metabolism* / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018045:Receptors, Oxytocin / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D018045:Receptors, Oxytocin; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters