GABA/glycine signaling during degeneration and regeneration of mouse hypoglossal nerves

Tatetsu, Masaharu; Kim, Jeong-Tae; Kina, Shinichiro; Sunakawa, Hajime; Takayama, Chitoshi

doi:10.1016/j.brainres.2012.01.048

Cited by 27 publications

(17 citation statements)

References 54 publications

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“…On P7, there was highly dense KCC2 expression in the medial and dorsal parts of the SL, and KCC2 expression remained dense in the other subnuclei. On P7, the expression pattern of KCC2 was similar to that seen in the 12 N of an adult mouse (Tatetsu et al, 2012). The fact that KCC2 immunoreactivity was increased in the SL during development could lend support to the notion that a KCC2-mediated decrease in [Cl À ] i in the SL plays a critical role in regulating tongue movement after birth.…”

Section: Discussionsupporting

confidence: 55%

KCC2-mediated regulation of respiration-related rhythmic activity during postnatal development in mouse medulla oblongata

et al. 2015

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Section: Discussionsupporting

confidence: 55%

KCC2-mediated regulation of respiration-related rhythmic activity during postnatal development in mouse medulla oblongata

et al. 2015

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“…ChAT has been extensively used to label cholinergic neurons in the ENS. To examine the immunoreactivity of epithelium for ChAT, indirect immunofluorescence staining was performed with an antibody against ChAT . ChAT was detected in the cytoplasm of epithelial cells throughout the villus (Fig.…”

Section: Resultsmentioning

confidence: 99%

Non‐neuronal acetylcholine as an endogenous regulator of proliferation and differentiation of Lgr5‐positive stem cells in mice

et al. 2014

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Non-neuronal acetylcholine (ACh) is predicted to function as a local cell signaling molecule. However, the physiological significance of the synthesis of non-neuronal ACh in the intestine remains unclear. Here, experiments using crypt-villus organoids that lack nerve and immune cells in culture led us to suggest that endogenous ACh is synthesized in the intestinal epithelium to evoke growth and differentiation of the organoids through activation of muscarinic ACh receptors (mAChRs). The extracts of the cultured organoids showed a noticeable capacity for ACh synthesis that was sensitive to a potent inhibitor of choline acetyltransferase. Imaging MS revealed endogenous ACh localized in the epithelial layer in mouse small intestinal epithelium in vivo, suggesting that there are non-neuronal resources of ACh. Treatment of organoids with carbachol downregulated the growth of organoids and the expression of marker genes for epithelial cells. On the other hand, antagonists for mAChRs enhanced the growth and differentiation of organoids, indicating the involvement of mAChRs in regulating the proliferation and differentiation of Lgr5-positive stem cells. Collectively, our data provide evidence that endogenous ACh released from intestinal epithelium maintains homeostasis of intestinal epithelial cell growth and differentiation via mAChRs in mice.

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“…The first study of KCC2 regulation on motoneurons following PNI was conducted in the dorsal motor nucleus of the vagus (DMV), where KCC2 mRNA was diminished by 3 d after vagal nerve axotomy in young rats (Nabekura et al, 2002). DMV neurons innervate postganglionic parasympathetic neurons rather than skeletal muscle, but these findings were later recapitulated in facial (Toyoda et al, 2003; Kim et al, 2018) and hypoglossal (Tatetsu et al, 2012) motoneurons following transection of the respective peripheral nerves. Several of these studies speculated on the eventual return of KCC2 mRNA (Toyoda et al, 2003) and protein (Tatetsu et al, 2012; Kim et al, 2018), but none analyzed this directly or whether it was dependent on successful target reinnervation.…”

Section: Discussionmentioning

confidence: 97%

“…DMV neurons innervate postganglionic parasympathetic neurons rather than skeletal muscle, but these findings were later recapitulated in facial (Toyoda et al, 2003; Kim et al, 2018) and hypoglossal (Tatetsu et al, 2012) motoneurons following transection of the respective peripheral nerves. Several of these studies speculated on the eventual return of KCC2 mRNA (Toyoda et al, 2003) and protein (Tatetsu et al, 2012; Kim et al, 2018), but none analyzed this directly or whether it was dependent on successful target reinnervation. Our study established that KCC2 recovery in axotomized motoneurons is correlated with successful axon regeneration and more specifically with re-innervation of NMJs, this mechanism could be shared by both brainstem and spinal motoneurons.…”

Section: Discussionmentioning

confidence: 97%

“…Isoform two of the potassium chloride cotransporter (KCC2) regulates intracellular chloride in most adult neurons; it defines the strength of inhibition (Payne et al, 2003; Kaila et al, 2014; Kahle and Delpire, 2016) and even the direction of membrane polarizations after opening of GABA A and glycine receptor chloride channels. KCC2 expression is downregulated in brainstem motoneurons following peripheral axotomy (Nabekura et al, 2002; Toyoda et al, 2003; Tatetsu et al, 2012; Kim et al, 2018) and results in spontaneous membrane depolarizations dependent on GABA A and NMDA receptor activation that trigger calcium entry through the opening of voltage-gated calcium channels (Toyoda et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Removal of the Potassium Chloride Co-Transporter from the Somatodendritic Membrane of Axotomized Motoneurons Is Independent of BDNF/TrkB Signaling But Is Controlled by Neuromuscular Innervation

Akhter

Griffith

English

et al. 2019

eNeuro

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The potassium-chloride cotransporter (KCC2) maintains the low intracellular chloride found in mature central neurons and controls the strength and direction of GABA/glycine synapses. We found that following axotomy as a consequence of peripheral nerve injuries (PNIs), KCC2 protein is lost throughout the somatodendritic membrane of axotomized spinal cord motoneurons after downregulation of kcc2 mRNA expression. This large loss likely depolarizes the reversal potential of GABA/glycine synapses, resulting in GABAergic-driven spontaneous activity in spinal motoneurons similar to previous reports in brainstem motoneurons. We hypothesized that the mechanism inducing KCC2 downregulation in spinal motoneurons following peripheral axotomy might be mediated by microglia or motoneuron release of BDNF and TrkB activation as has been reported on spinal cord dorsal horn neurons after nerve injury, motoneurons after spinal cord injury (SCI), and in many other central neurons throughout development or a variety of pathologies. To test this hypothesis, we used genetic approaches to interfere with microglia activation or delete bdnf from specifically microglia or motoneurons, as well as pharmacology (ANA-12) and pharmacogenetics (F616A mice) to block TrkB activation. We show that KCC2 dysregulation in axotomized motoneurons is independent of microglia, BDNF, and TrkB. KCC2 is instead dependent on neuromuscular innervation; KCC2 levels are restored only when motoneurons reinnervate muscle. Thus, downregulation of KCC2 occurs specifically while injured motoneurons are regenerating and might be controlled by target-derived signals. GABAergic and glycinergic synapses might therefore depolarize motoneurons disconnected from their targets and contribute to augment motoneuron activity known to promote motor axon regeneration. Significance StatementThe neuronal potassium-chloride cotransporter KCC2 is dysregulated after numerous types of neuronal injuries and has been related to neuronal dysfunction, hyperalgesia and spasticity. In this study, we investigated KCC2 regulation on spinal motoneurons with axons injured during peripheral nerve transections. We illustrate that KCC2 loss on axotomized motoneurons occurs at the transcriptional level. This loss differs in time course, completeness and signaling mechanisms from KCC2 dysregulation in other neurons after various pathologies or in motoneurons after spinal cord injury (SCI). In contrast, KCC2 loss on axotomized motoneurons relates to muscle innervation, suggesting a dependence on target-derived signals. We argue that KCC2 loss in axotomized motoneurons may be part of the response that facilitates regeneration of motor axons in the periphery.

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GABA/glycine signaling during degeneration and regeneration of mouse hypoglossal nerves

Cited by 27 publications

References 54 publications

KCC2-mediated regulation of respiration-related rhythmic activity during postnatal development in mouse medulla oblongata

KCC2-mediated regulation of respiration-related rhythmic activity during postnatal development in mouse medulla oblongata

Non‐neuronal acetylcholine as an endogenous regulator of proliferation and differentiation of Lgr5‐positive stem cells in mice

Removal of the Potassium Chloride Co-Transporter from the Somatodendritic Membrane of Axotomized Motoneurons Is Independent of BDNF/TrkB Signaling But Is Controlled by Neuromuscular Innervation

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