The Timing of the Excitatory-to-Inhibitory GABA Switch Is Regulated by the Oxytocin Receptor via KCC2.

Marianna Leonzino,Marta Busnelli,Claudia Verderio,Bice Chini,Flavia Antonucci,Michele Mazzanti

doi:10.1016/j.celrep.2016.03.013

Marianna Leonzino, Marta Busnelli + Show 4 more

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SummaryOxytocin 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.

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To correctly shape neuronal circuits, postnatal brain development requires a finely tuned balance between excitation and inhibition (E/I)
Our present findings indicate that Oxytocin and its receptor (Oxtr) is essential for the proper developmental increase of K+-ClÀ cotransporter 2 (KCC2) and for the consequent switch in g-aminobutyric acid (GABA) activity
To disclose any temporal difference in the occurrence of the GABA switch between OxtrÀ/À and Oxtr+/+ cultures, we evaluated, during development, the percentage of neurons showing GABA-induced Ca2+ transients and the amplitude of such responses (Figures 1C and 1D)

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To correctly shape neuronal circuits, postnatal brain development requires a finely tuned balance between excitation and inhibition (E/I). Impairments of this balance have been proposed to underlie many neurodevelopmental brain disorders including autism. The most critical determinants of this balance are glutamate and g-aminobutyric acid (GABA), respectively the main excitatory and inhibitory neurotransmitters. In immature neurons, both glutamate and GABA, by inducing depolarization and Ca2+ influx through voltage-operated Ca2+ channels (VOCC), work in synergy on proliferation, migration, maturation, and differentiation. The proper timing of GABA transition from depolarizing to hyperpolarizing is fundamental for a correct development of the brain (Ben-Ari et al, 1989)

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