Developmental Formation of the GABAergic and Glycinergic Networks in the Mouse Spinal Cord

Shimizu-Okabe, Chigusa; Kobayashi, Shiori; Kim, Jeong-Tae; Kosaka, Yoshinori; Sunagawa, Masanobu; Okabe, Akihito; Takayama, Chitoshi

doi:10.3390/ijms23020834

Cited by 9 publications

(4 citation statements)

References 181 publications

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“…In the spinal cord ventral horn, VGLUT1 predominantly labels excitatory glutamatergic terminals from muscle afferents 43 , 44 , whilst GAD67 labels inhibitory GABAergic terminals from local interneurons that are likely activated by both sensory and descending inputs 45 . Motoneurons also receive inhibitory input from glycinergic terminals but GlyT2 immunohistochemistry suggests these do not undergo significant reorganization following SNC (Supp.…”

Section: Discussionmentioning

confidence: 99%

KCC2 downregulation after sciatic nerve injury enhances motor function recovery

Cheung

Toda

Narushima

et al. 2023

Sci Rep

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Injury to mature neurons induces downregulated KCC2 expression and activity, resulting in elevated intracellular [Cl−] and depolarized GABAergic signaling. This phenotype mirrors immature neurons wherein GABA-evoked depolarizations facilitate neuronal circuit maturation. Thus, injury-induced KCC2 downregulation is broadly speculated to similarly facilitate neuronal circuit repair. We test this hypothesis in spinal cord motoneurons injured by sciatic nerve crush, using transgenic (CaMKII-KCC2) mice wherein conditional CaMKIIα promoter-KCC2 expression coupling selectively prevents injury-induced KCC2 downregulation. We demonstrate, via an accelerating rotarod assay, impaired motor function recovery in CaMKII-KCC2 mice relative to wild-type mice. Across both cohorts, we observe similar motoneuron survival and re-innervation rates, but differing post-injury reorganization patterns of synaptic input to motoneuron somas—for wild-type, both VGLUT1-positive (excitatory) and GAD67-positive (inhibitory) terminal counts decrease; for CaMKII-KCC2, only VGLUT1-positive terminal counts decrease. Finally, we recapitulate the impaired motor function recovery of CaMKII-KCC2 mice in wild-type mice by administering local spinal cord injections of bicuculline (GABAA receptor blockade) or bumetanide (lowers intracellular [Cl−] by NKCC1 blockade) during the early post-injury period. Thus, our results provide direct evidence that injury-induced KCC2 downregulation enhances motor function recovery and suggest an underlying mechanism of depolarizing GABAergic signaling driving adaptive reconfiguration of presynaptic GABAergic input.

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Section: Discussionmentioning

confidence: 99%

KCC2 downregulation after sciatic nerve injury enhances motor function recovery

Cheung

Toda

Narushima

et al. 2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the spinal cord ventral horn, VGLUT1 predominantly labels excitatory glutamatergic terminals from muscle afferents [45,46], whilst GAD67 labels inhibitory GABAergic terminals from local interneurons that are likely activated by both sensory and descending inputs [47]. Motoneurons also receive inhibitory input from glycinergic terminals but GlyT2 immunohistochemistry suggests these do not undergo signi cant reorganization following SNC (Supp.…”

Section: Discussionmentioning

confidence: 99%

KCC2 downregulation after sciatic nerve injury enhances motor function recovery

Cheung

Toda

Narushima

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Injury to mature neurons induces downregulated KCC2 expression and activity, resulting in elevated intracellular [Cl−] and depolarized GABAergic signaling. This phenotype mirrors immature neurons wherein GABA-evoked depolarizations facilitate neuronal circuit maturation. Thus, injury-induced KCC2 downregulation is broadly speculated to similarly facilitate neuronal circuit repair. We test this hypothesis in spinal cord motoneurons injured by sciatic nerve crush, using transgenic (CaMKII-KCC2) mice wherein conditional CaMKIIα promoter-KCC2 expression coupling selectively prevents injury-induced KCC2 downregulation. We demonstrate, via an accelerating rotarod assay, impaired motor function recovery in CaMKII-KCC2 mice relative to wild-type mice. Across both cohorts, we observe similar motoneuron survival and re-innervation rates, but differing post-injury reorganization patterns of synaptic input to motoneuron somas – for wild-type, both VGLUT1-positive (excitatory) and GAD67-positive (inhibitory) terminal counts decrease; for CaMKII-KCC2, only VGLUT1-positive terminal counts decrease. Finally, we recapitulate the impaired motor function recovery of CaMKII-KCC2 mice in wild-type mice via local spinal cord injections of bicuculline (GABAA receptor blockade) or bumetanide (lowers intracellular [Cl−] by NKCC1 blockade) during the early post-injury period. Thus, our results provide direct evidence that injury-induced KCC2 downregulation enhances motor function recovery and suggest an underlying mechanism of depolarizing GABAergic signaling driving adaptive neuronal circuit reconfiguration that preserves appropriate excitation-inhibition balance.

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“…The Gamma-aminobutyric acid (GABA)ergic system is an integral component of neuronal circuits also involved in processing sensory information. As a main inhibitory neurotransmitter, GABA is widely expressed in interneurons of the spinal cord and presents up to 40% of neurons in laminae I, II, and III ( Polgár et al, 2003 ; Shimizu-Okabe et al, 2022 ). Inhibitory interneurons have various functions, and reduction of inhibitory GABAergic neurotransmission can cause disinhibition of excitatory transmission, which contributes to sensory hypersensitivity and spontaneous pain ( Sandkühler, 2009 ; Comitato and Bardoni, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spinal GABA transporter 1 contributes to evoked-pain related behavior but not resting pain after incision injury

Pradier,

Segelcke,

Reichl

et al. 2023

Front. Mol. Neurosci.

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The inhibitory function of GABA at the spinal level and its central modulation in the brain are essential for pain perception. However, in post-surgical pain, the exact mechanism and modes of action of GABAergic transmission have been poorly studied. This work aimed to investigate GABA synthesis and uptake in the incisional pain model in a time-dependent manner. Here, we combined assays for mechanical and heat stimuli-induced withdrawal reflexes with video-based assessments and assays for non-evoked (NEP, guarding of affected hind paw) and movement-evoked (MEP, gait pattern) pain-related behaviors in a plantar incision model in male rats to phenotype the effects of the inhibition of the GABA transporter (GAT-1), using a specific antagonist (NO711). Further, we determined the expression profile of spinal dorsal horn GAT-1 and glutamate decarboxylase 65/67 (GAD65/67) by protein expression analyses at four time points post-incision. Four hours after incision, we detected an evoked pain phenotype (mechanical, heat and movement), which transiently ameliorated dose-dependently following spinal inhibition of GAT-1. However, the NEP-phenotype was not affected. Four hours after incision, GAT-1 expression was significantly increased, whereas GAD67 expression was significantly reduced. Our data suggest that GAT-1 plays a role in balancing spinal GABAergic signaling in the spinal dorsal horn shortly after incision, resulting in the evoked pain phenotype. Increased GAT-1 expression leads to increased GABA uptake from the synaptic cleft and reduces tonic GABAergic inhibition at the post-synapse. Inhibition of GAT-1 transiently reversed this imbalance and ameliorated the evoked pain phenotype.

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Developmental Formation of the GABAergic and Glycinergic Networks in the Mouse Spinal Cord

Cited by 9 publications

References 181 publications

KCC2 downregulation after sciatic nerve injury enhances motor function recovery

KCC2 downregulation after sciatic nerve injury enhances motor function recovery

KCC2 downregulation after sciatic nerve injury enhances motor function recovery

Spinal GABA transporter 1 contributes to evoked-pain related behavior but not resting pain after incision injury

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