WNK3 Maintains the GABAergic Inhibitory Tone, Synaptic Excitation and Neuronal Excitability via Regulation of KCC2 Cotransporter in Mature Neurons

Lim, Wee Meng; Chin, Eunice W. M.; Tang, Bor Luen; Chen, Tingting; Goh, Eyleen L. K.

doi:10.3389/fnmol.2021.762142

Cited by 6 publications

(2 citation statements)

References 89 publications

(137 reference statements)

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“…Most notably, it was shown that membrane levels of specific potassium channels are regulated via KCC2 (Goutierre et al, 2019) and the chloride-dependent kinase WNK3 (Sinha et al, 2022), and it will be important to further examine the role of various chloride channels in membrane excitability (Jentsch, 2016; Jentsch and Pusch, 2018; Akita and Fukuda, 2020). Interestingly, effects seem to strongly depend on cell type (Seja et al, 2012) and timing of the chloride manipulation (Lim et al, 2021; Sinha et al, 2022). The changes in excitability that we observed at DIV21 may therefore reflect a complex sequence of subtle adaptations of ion channel distribution that is specific per cell type.…”

Section: Discussionmentioning

confidence: 99%

Delaying the GABA shift indirectly affects membrane properties in the developing hippocampus

Peerboom

Kater

Jonker

et al. 2023

Preprint

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During the first two postnatal weeks intraneuronal chloride concentrations in rodents gradually decrease, causing a shift from depolarizing to hyperpolarizing γ-aminobutyric acid (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 remain 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-day old mice by treating the cultures for one 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 day in vitro (DIV) 9. 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, fourteen days after the VU treatment had ended (DIV21), we observed an increased frequency of spontaneous inhibitory post-synaptic 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 to 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.

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Section: Discussionmentioning

confidence: 99%

Delaying the GABA shift indirectly affects membrane properties in the developing hippocampus

Peerboom

Kater

Jonker

et al. 2023

Preprint

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“…It will also be important to further examine the role of various chloride channels in membrane excitability (Jentsch, 2016;Akita and Fukuda, 2020). Interestingly, effects seem to strongly depend on cell type and timing of the chloride manipulation (Lim et al, 2021;. The changes in excitability that we observed at DIV21 may therefore reflect a complex sequence of subtle adaptations of ion channel distribution that is likely specific per cell type and per brain region.…”

Section: Discussionmentioning

confidence: 87%

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Our brain is a fascinatingly complex organ comprised of a network of millions of brain cells (neurons), and their connections (synapses). Neurons come in two types: excitatory and inhibitory. When an excitatory neuron is active, it will send positive electrical signals through its excitatory synapses to the next neurons in the network. When an inhibitory neuron is active, it will provide subsequent neurons with negative electrical signals via its inhibitory synapses. All positive and negative signals simultaneously received by a brain cell, determine whether the cell will become active itself and will pass its electrical signals on to the next cells in the network. The development of the brain starts already in the womb. Genes provide the blueprint for the first steps in network formation. In addition, network development is directed by spontaneous neuronal activity generated by excitatory signaling. Excitatory signals allow the fetal neuronal network to grow quickly by stimulating neuronal proliferation, synapse formation and synaptic strengthening. At this time, excitation is mainly provided by a substance called gamma-aminobutyric acid or GABA. Only later on, sensory experiences start affecting the electrical activity in the network. Around the same time, GABA is changing from being excitatory, to inhibitory. Excitation is now provided by another signaling molecule, called glutamate. Inhibition enables the brain to handle an enormous amount of external stimuli in a controlled manner by filtering out irrelevant inputs and only passing on relevant stimuli. The gradual developmental change in the function of GABA from excitation to inhibition is called the GABA shift. During my PhD, I studied the GABA shift in brain slices from mice. Brain development in mice and humans is very similar, though much faster in mice. In comparison: in humans, GABA shifts during the last three months of pregnancy, in mice during the first two weeks after birth. To measure the GABA shift in murine brain slices, we tested a new sensor. We could discern the GABA shift by comparing dozens of neurons in slices of different ages. In addition, we used the sensor to investigate the effect of early life stress on the GABA shift. Stress seemed to delay the GABA shift in young mice. This study underlines the role of experience in brain development, which allows for adaptability, but also leads to vulnerability. We also investigated the consequences of accelerating and delaying the GABA shift. Previous studies have shown that the excitatory GABA promotes synapse formation. Therefore, we expected that a delayed GABA shift would result in an overproduction of synapses. However, this is not what we observed when we manipulated the GABA shift in slices from one week-old mice. We saw that a delayed GABA shift did not affect synapses, but found indirect changes in the neurons’ electrical properties. This work is important for neurodevelopmental disorders such as autism, in which the GABA shift often seems delayed. Our research shows that such a delay affects further brain development.

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GABAergic Neurotransmission Abnormalities in Pharmacoresistant Epilepsy: Experimental and Human Studies

Orozco-Suárez,

Feria-Romero,

Ureña-Guerrero

et al. 2023

Pharmacoresistance in Epilepsy

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WNK3 Maintains the GABAergic Inhibitory Tone, Synaptic Excitation and Neuronal Excitability via Regulation of KCC2 Cotransporter in Mature Neurons

Cited by 6 publications

References 89 publications

Delaying the GABA shift indirectly affects membrane properties in the developing hippocampus

Delaying the GABA shift indirectly affects membrane properties in the developing hippocampus

Need for negativity

GABAergic Neurotransmission Abnormalities in Pharmacoresistant Epilepsy: Experimental and Human Studies

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