Variable colocalisation of GABAA receptor subunits and glycine receptors on neurons in the human hypoglossal nucleus

Waldvogel, Henry J.; Biggins, F.M.; Singh, Abhilasha; Arasaratnam, Christine J.; Faull, Richard L. M.

doi:10.1016/j.jchemneu.2019.02.005

Cited by 4 publications

(4 citation statements)

References 95 publications

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“…Mutant GlyRs may disrupt the function of GABA A Rs in the same neuron since the preponderance of evidence has indicated a wide colocalization of GlyRs and GABA A Rs in brainstem neurons (Muller et al., 2004, Muller et al., 2006, Lorenzo et al., 2006, Lorenzo et al., 2007, Waldvogel et al., 2019). Next, we investigated whether the GlyRα 1 mutations could induce GABA A R deficiency if these receptors were co-expressed in HEK-293 cells.…”

Section: Resultsmentioning

confidence: 99%

Human Hyperekplexic Mutations in Glycine Receptors Disinhibit the Brainstem by Hijacking GABAA Receptors

Zou

Chen

et al. 2019

iScience

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Summary Hyperekplexia disease is usually caused by naturally occurring point mutations in glycine receptors (GlyRs). However, the γ-aminobutyric acid type A receptor (GABA A R) seems to be also involved regarding the therapeutic basis for hyperekplexia using benzodiazepines, which target GABA A Rs but not GlyRs. Here, we show that the function of GABA A Rs was significantly impaired in the hypoglossal nucleus of hyperekplexic transgenic mice. Such impairment appeared to be mediated by interaction between GABA A R and mutant GlyR. The GABA A R dysfunction was caused only by mutant GlyR consisting of homomeric α 1 subunits, which locate primarily at pre- and extra-synaptic sites. In addition, the rescue effects of diazepam were attenuated by Xli-093, which specifically blocked diazepam-induced potentiation on α 5 -containing GABA A R, a major form of pre- and extra-synaptic GABA A R in the brainstem. Thus, our results suggest that the pre- and extra-synaptic GABA A Rs could be a potential therapeutic target for hyperekplexia disease caused by GlyR mutations.

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Section: Resultsmentioning

confidence: 99%

Human Hyperekplexic Mutations in Glycine Receptors Disinhibit the Brainstem by Hijacking GABAA Receptors

Zou

Chen

et al. 2019

iScience

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“…Previous studies have shown that GABA and glycine neurotransmitters are colocalized in interneurons in the cerebellar cortex (Crook et al, 2006; Simat et al, 2007) and retina (Grunert, 2000). Coexpression of GABA A and glycine receptor subunits have also been found in motor neurons in the XII and spinal cord (Carlton & Hayes, 1990; Christenson et al, 1993; Shupliakov et al, 1996; Tatetsu et al, 2012; Waldvogel et al, 2019), and GABA/glycine are known to be essential during neuronal development and regeneration, although their functional consequences in regulating medullary neurons are still not clear, especially in RTT. Our observation in the present study strongly suggests that in the medulla oblongata GABA and glycine seem to play equally important roles in the inhibitory neurotransmission, and medullary neurons seem to rely more on glycine signaling in the mouse model of RTT.…”

Section: Discussionmentioning

confidence: 99%

“…They regulate the upper airway dimension, tongue movements, and swallowing. The XII neurons are modulated by respiratory neuronal networks with regular respiratory bursting activity and provide changes in tongue muscular tones according to the breathing rhythm (Petukhova et al, 2018; Waldvogel et al, 2019). The DMNV contains visceral motor neurons constituting the major vagus efferents.…”

Section: Introductionmentioning

confidence: 99%

“…The hyperexcitability of the brainstem neurons is related to a deficiency in GABAergic synaptic inhibition, which as well as several RTT‐types of breathing abnormalities can be improved after the administration of GABA re‐uptake blockers or GABA receptor agonists (Wu et al, 2019; Zhong et al, 2016, 2017). Glycine is another inhibitory neurotransmitter playing a role in the spinal cord and the retina (Dhingra et al, 2019; Han et al, 2016; Waldvogel et al, 2019). Glycine plays an inhibitory role in the brainstem (Fortuna et al, 2019), whereas it is still unclear how the Mecp2 disruption affects glycine signaling.…”

Section: Introductionmentioning

confidence: 99%

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Dual synaptic inhibitions of brainstem neurons by GABA and glycine with impact on Rett syndrome

Xing

Cui

Johnson

et al. 2020

Journal Cellular Physiology

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Rett syndrome (RTT) is a neurodevelopmental disease caused mostly by mutations in the MECP2 gene. People with RTT show breathing dysfunction attributable to the high rate of sudden death. Previous studies have shown that insufficient GABA synaptic inhibition contributes to the breathing abnormalities in mouse models of RTT, while it remains elusive how the glycine system is affected. We found that optogenetic stimulation of GAD‐expressing neurons in mice produced GABAergic and glycinergic postsynaptic inhibitions of neurons in the hypoglossal nucleus (XII) and the dorsal motor nucleus of vagus (DMNV). By sequential applications of bicuculline and strychnine, such inhibition appeared approximately 44% GABAAergic and 52% glycinergic in XII neurons, and approximately 49% GABAAergic and 46% glycinergic in DMNV neurons. Miniature inhibitory postsynaptic potentials (mIPSCs) in these neurons were approximately 47% GABAAergic and 49% glycinergic in XII neurons, and approximately 48% versus 50% in DMNV neurons, respectively. Consistent with the data, our single‐cell polymerase chain reaction studies indicated that transcripts of GABAA receptor γ2 subunit (GABAARγ2) and glycine receptor β subunit (GlyRβ) were simultaneously expressed in these cells. In MeCP2R168X mice, proportions of GABAAergic and glycinergic mIPSCs became approximately 28% versus 69% in XII neurons, and approximately 31% versus 66% in DMNV cells. In comparison with control mice, the GABAAergic and glycinergic mIPSCs decreased significantly in the XII and DMNV neurons from the MeCP2R168X mice, so did the transcripts of GABAARγ2 and GlyRβ. These results suggest that XII and DMNV neurons adopt dual GABAAergic and glycinergic synaptic inhibitions, and with Mecp2 disruption these neurons rely more on glycinergic synaptic inhibition.

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The dorsal and the ventral side of hypoglossal motor nucleus showed different response to chronic intermittent hypoxia in rats

et al. 2020

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Variable colocalisation of GABAA receptor subunits and glycine receptors on neurons in the human hypoglossal nucleus

Cited by 4 publications

References 95 publications

Human Hyperekplexic Mutations in Glycine Receptors Disinhibit the Brainstem by Hijacking GABAA Receptors

Human Hyperekplexic Mutations in Glycine Receptors Disinhibit the Brainstem by Hijacking GABAA Receptors

Dual synaptic inhibitions of brainstem neurons by GABA and glycine with impact on Rett syndrome

The dorsal and the ventral side of hypoglossal motor nucleus showed different response to chronic intermittent hypoxia in rats

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