Delaying the GABA Shift Indirectly Affects Membrane Properties in the Developing Hippocampus

Carlijn Peerboom, Sam de Kater, Nikki Jonker, Marijn P.J.M. Rieter, Tessel Wijne, Corette J. Wierenga

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

During the first two postnatal weeks, intraneuronal chloride concentrations in rodents gradually decrease, causing a shift from depolarizing to hyperpolarizing GABA responses. The postnatal GABA shift is delayed in rodent models for neurodevelopmental disorders and in human patients, but the impact of a delayed GABA shift on the developing brain remains obscure. Here we examine the direct and indirect consequences of a delayed postnatal GABA shift on network development in organotypic hippocampal cultures made from 6- to 7-d-old mice by treating the cultures for 1 week with VU0463271, a specific inhibitor of the chloride exporter KCC2. We verified that VU treatment delayed the GABA shift and kept GABA signaling depolarizing until DIV9. We found that the structural and functional development of excitatory and inhibitory synapses at DIV9 was not affected after VU treatment. In line with previous studies, we observed that GABA signaling was already inhibitory in control and VU-treated postnatal slices. Surprisingly, 14 d after the VU treatment had ended (DIV21), we observed an increased frequency of spontaneous inhibitory postsynaptic currents in CA1 pyramidal cells, while excitatory currents were not changed. Synapse numbers and release probability were unaffected. We found that dendrite-targeting interneurons in the stratum radiatum had an elevated resting membrane potential, while pyramidal cells were less excitable compared with control slices. Our results show that depolarizing GABA signaling does not promote synapse formation after P7, and suggest that postnatal intracellular chloride levels indirectly affect membrane properties in a cell-specific manner.
Original languageEnglish
Pages (from-to)5483-5500
Number of pages18
JournalJournal of Neuroscience
Volume43
Issue number30
DOIs
Publication statusPublished - 12 Jul 2023

Keywords

  • brain development
  • chloride
  • homeostasis
  • membrane excitability
  • neurodevelopmental disorders
  • synapse formation

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