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• GABA roles in development, plastisity and regeneration

• Molecular and morphologica analysis in GABAergic Signaling in the Developing Brain

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• Altered Distribution of Inhibitory Synaptic Terminals in Reeler Cerebellum with Special Reference to Malposition of GABAergic Neurons

  1994.09

  DOI

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Published Papers 【 display / non-display 】

• Number of subfields of the rat dorsal subiculum defined by NOS and PCP4 immunoreactivity changes according to different levels of observation

  Ishihara, Y; Sato, F; Guinet, A; Grosser, S; Vida, I; Kubota, Y; Takayama, C

  NEUROSCIENCE ( Neuroscience )  568   285 - 297   2025.03 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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• Reduced Gene Expression of KCC2 Accelerates Axonal Regeneration and Reduces Motor Dysfunctions after Tibial Nerve Severance and Suturing

  Ando, H; Shimizu-Okabe, C; Okura, N; Yafuso, T; Kosaka, Y; Kobayashi, S; Okabe, A; Takayama, C

  NEUROSCIENCE ( Neuroscience )  551   55 - 68   2024.07 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

  　View Summary

  Gamma-aminobutyric acid and glycine (GABA/Gly) are predominantly inhibitory neurotransmitters in the mature central nervous system; however, they mediate membrane potential depolarization during development. These differences in actions depend on intracellular Cl- concentrations ([Cl-]i), which are primarily regulated by potassium chloride cotransporter 2 (KCC2). After nerve injury, KCC2 expression markedly decreases and GABA/Gly mediate depolarization. Following nerve regeneration, KCC2 expression recovers and GABA/Gly become inhibitory, suggesting that KCC2 reduction and GABA/Gly excitation may be crucial for axonal regeneration. To directly clarify their involvement in regeneration, we analyzed recovery processes after tibial nerve severance and suturing between heterozygous KCC2 knockout mice (HT), whose KCC2 levels are halved, and their wild-type littermates (WT). Compared with WT mice, the sciatic functional index-indicating lower limb motor function-was significantly higher until 28 days after operation (D28) in HT mice. Furthermore, at D7, many neurofilament-positive fibers were elongated into the distal part of the sutured nerve in HT mice only, and myelinated axonal density was significantly higher at D21 and D28 in HT animals. Electron microscopy and galanin immunohistochemistry indicated a shorter nerve degeneration period in HT mice. Moreover, a less severe decrease in choline acetyltransferase was observed in HT mice. These results suggest that nerve degeneration and regeneration proceed more rapidly in HT mice, resulting in milder motor dysfunction. Via similar microglial activation, nerve surgery may reduce KCC2 levels more rapidly in HT mice, followed by earlier increased [Cl-]i and longer-lasting GABA/Gly excitation. Taken together, reduced KCC2 may accelerate nerve regeneration via GABA/Gly excitation.

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• Action Sequence Learning Is Impaired in Genetically Modified Mice with the Suppressed GABAergic Transmission from the Thalamic Reticular Nucleus to the Thalamus

  Ohno-Shosaku, T; Yoneda, M; Maejima, T; Wang, MH; Kikuchi, Y; Onodera, K; Kanazawa, Y; Takayama, C; Mieda, M

  NEUROSCIENCE ( Neuroscience )  532   87 - 102   2023.11 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

  　View Summary

  The thalamic reticular nucleus (TRN) is a thin sheet of GABAergic neurons surrounding the thalamus, and it regulates the activity of thalamic relay neurons. The TRN has been reported to be involved in sensory gating, attentional regulation, and some other functions. However, little is known about the contribution of the TRN to sequence learning. In the present study, we examined whether the TRN is involved in reward-based learning of action sequence with no eliciting stimuli (operant conditioning), by analyzing the performance of male and female Avp-Vgat-/- mice (Vgatflox/flox mice crossed to an Avp-Cre driver line) on tasks conducted in an operant box having three levers. Our histological and electrophysiological data demonstrated that in adult Avp-Vgat-/- mice, vesicular GABA transporter (VGAT) was absent in most TRN neurons and the GABAergic transmission from the TRN to the thalamus was largely suppressed. The performance on a task in which mice needed to press an active lever for food reward showed that simple operant learning of lever pressing and learning of win-stay and lose-shift strategies are not affected in Avp-Vgat-/- mice. In contrast, the performance on a task in which mice needed to press three levers in a correct order for food reward showed that learning of the order of lever pressing (action sequence learning) was impaired in Avp-Vgat-/- mice. These results suggest that the TRN plays an important role in action sequence learning.

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• KCC2 downregulation after sciatic nerve injury enhances motor function recovery

  Cheung, DL; Toda, T; Narushima, M; Eto, K; Takayama, C; Ooba, T; Wake, H; Moorhouse, AJ; Nabekura, J

  SCIENTIFIC REPORTS ( Scientific Reports )  13 ( 1 ) 7871 - 7871   2023.05 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

  　View Summary

  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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• Specific Expression of KCC2 in the α Cells of Normal and Type 1 Diabetes Model Mouse Pancreatic Islets.

  Shimizu-Okabe C, Okada S, Okamoto S, Masuzaki H, Takayama C

  Acta histochemica et cytochemica ( 日本組織細胞化学会 )  55 ( 1 ) 47 - 56   2022.02 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  <p>Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the mature brain; however, it acts excitatory during development. This difference in action depends on the intra­cellular chloride ion concentration, primarily regulated by potassium chloride co-transporter2 (KCC2). Sufficient KCC2 expression results in its inhibitory action. GABA is also abundant in pancreatic islets, where it acts differentially on the islet cells, and is involved in carbohydrate metabolism. However, the mechanisms underlying the differential action remain unknown. We performed immunohistochemistry for glutamic acid decarboxylase (GAD), a synthetic enzyme for GABA, and KCC2 in normal adult islets. GAD was co-localized with insulin in β cells, whereas KCC2 was expressed in glucagon-positive α cells. These results are in line with previous observations that GABA decreases glucagon release but increases insulin release, and suggest that GABA and insulin may work together in reducing blood glucose levels under hyperglycemia. Next, we examined the streptozotocin-induced type1 diabetes mellitus mouse model. GAD and insulin expression levels were markedly decreased. KCC2 was expressed in glucagon-positive cells, whereas insulin- and somatostatin-positive cells were KCC2-negative. These findings suggest that in diabetes model, reduced GABA release may cause disinhibition of glucagon release, resulting in increased blood sugar levels and the maintenance of hyperglycemic state.</p>

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• Factors Affecting Neurodevelopment

  Shiori Kobayashi, Chigusa Shimizu-Okabe, Jeongtae Kim, Yoshinori Kosaka, Masanobu Sunagawa, Akihito Okabe, Chitoshi Takayama ( Part: Multiple Authorship ,  Development of the GABAergic network in the mouse spinal cord )

  Academic Press is an imprint of Elsevier  2021

  　View Summary

  Gamma-amino butyric acid (GABA) is one of the predominant inhibitory neurotransmitters in the spinal cord and negatively regulates neuronal activity. In this chapter, we describe the mature GABAergic system in the spinal cord and its developmental process from the viewpoints of GABAergic neurons and terminals, GABA receptors, GABAergic action, and the GABA removal system based on morphological studies. A ventral-to-dorsal developmental direction exists in the localization of GABAergic neurons and terminals, shift of GABAergic action from excitatory to inhibitory, and formation of the GABA removal system. Changes in GABAergic action and maturation of the GABA removal system parallel the formation of GABAergic synapses. In the ventral horn, the number of the GABAergic synapses peaks on the day of birth, and these synapses gradually shift to glycinergic synapses after birth. In the dorsal horn, GABAergic synapses continue to increase in number until postnatal day 21, and some become GABA and glycine coreleasing synapses during postnatal development.

• GABAergic signaling in the developing cerebellum. In "GABA in autism and related disorders.(Dhossche D,Ed)"

  Takayama C ( Part: Single Author )

  Academic Press  2005.01

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• wx/ae米は腸内環境を改善し,脂質の排泄を促進する

  清水 千草, 小林 しおり, 佐瀬 英俊, 小塚 智沙代, 宮崎 悠, 新垣 正悟, 小倉 裕太, 益崎 裕章, 高山 千利

  肥満研究 ( (一社)日本肥満学会 )  23 ( Suppl. ) 208 - 208   2017.09

   

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• Grant-in-Aid for Scientific Research(C)

  Project Year: 2021.04  -  2024.03 

  Direct: 3,200,000 (YEN)  Overheads: 4,160,000 (YEN)  Total: 960,000 (YEN)

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2021.04  -  2024.03 

  Direct: 3,200,000 (YEN)  Overheads: 4,160,000 (YEN)  Total: 960,000 (YEN)

• Relationship between GABA release and GABAergic action in the spinal cord to the development of fetal motor function

  Grant-in-Aid for Scientific Research(C)

  Project Year: 2018.04  -  2022.03 

  Investigator(s): Chigusa Shimizu 

  Direct: 3,400,000 (YEN)  Overheads: 4,420,000 (YEN)  Total: 1,020,000 (YEN)

  　View Summary

  The release of the inhibitory transmitter GABA and the relationship between its inhibitory response and the development of fetal motor function were investigated by focusing on the anterior horn of the spinal cord, which is responsible for the output of motor information, clarifying the GABAergic neural architecture and examining body movement activity similar to fetal movement using spinal cord specimens with forelimbs. In addition, another inhibitory transmitter, glycine, was examined. The results showed that GABAergic innervation was initially formed, then co-emerged with glycine and finally became predominantly glycinergic. The results showed that the waveforms were different when GABA and glycine were administered in response to motor activity. The inhibitory responses of GABA and glycine were found to play an important role in the development of fetal motor function.

• Relationship between GABA release and GABAergic action in the spinal cord to the development of fetal motor function

  Grant-in-Aid for Scientific Research(C)

  Project Year: 2018.04  -  2022.03 

  Investigator(s): Chigusa Shimizu 

  Direct: 3,400,000 (YEN)  Overheads: 4,420,000 (YEN)  Total: 1,020,000 (YEN)

  　View Summary

  The release of the inhibitory transmitter GABA and the relationship between its inhibitory response and the development of fetal motor function were investigated by focusing on the anterior horn of the spinal cord, which is responsible for the output of motor information, clarifying the GABAergic neural architecture and examining body movement activity similar to fetal movement using spinal cord specimens with forelimbs. In addition, another inhibitory transmitter, glycine, was examined. The results showed that GABAergic innervation was initially formed, then co-emerged with glycine and finally became predominantly glycinergic. The results showed that the waveforms were different when GABA and glycine were administered in response to motor activity. The inhibitory responses of GABA and glycine were found to play an important role in the development of fetal motor function.

• Grant-in-Aid for Scientific Research(C)

  Project Year: 2017.04  -  2020.03 

  Direct: 3,800,000 (YEN)  Overheads: 1,140,000 (YEN)  Total: 4,940,000 (YEN)

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Social Activity 【 display / non-display 】

Social Activity 【 display / non-display 】

• University of the Ryukyus 

  2005.04

  -

  2024.03

• 2004.04