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Séminaire impromptu - Yun WANGBoth functional and structural KCC2 involve in epileptogenesis

Abstract :

Epilepsy is one of the most common serious neurological disorders affecting about 50 million people globally (WHO 2017). It is a group of neurological diseases characterized by epileptic seizures, which are episodes that can vary from brief and nearly undetectable to long periods of vigorous shaking, due to episodes of excessive electrical discharges in a group of brain cells. However, it is unknown under which circumstances the brain shifts into the activity of a seizure with its excessive synchronization. One of the mechanisms of epilepsy is either the up-regulation of excitatory circuits or down-regulation of inhibitory circuits, or both, following the unknown reasons, such as an injury to the brain, which leads to the decreased resistance of excitatory neurons to fire.

GABAA receptor-mediated inhibition depends on the maintenance of low level intracellular [Cl] concentration, which in adult depends on neuron specific K+-Cl- cotransporter-2 (KCC2). KCC2 has been found downregulated in both epileptic patients and various epileptic animal models. However, the temporal relationship between KCC2 downregulation and seizure induction and its relationship with the epileptogenesis is still unclear. In first part of this study, we focused on to explore the temporal relationship and the influence of KCC2 downregulation on epileptiform bursting activity induction, and our findings demonstrated that altered expression of KCC2 is not the consequence, but likely is the contributing factor for induction of epileptic seizure. In the second part of this study, we tempted to establish the relationship between membrane KCC2 and the excitatory synapse reorganization during epileptogenesis, and our preliminary experiment evidence indicated that the structral KCC2 is also an important factor in the progress of epileptogenesis.

 

Selected publications

1. Chen L, Wan L, Wu Z, Ren W, Huang Y, Qian B, Wang Y* (2017) KCC2 downregulation facilitates epileptic seizures. Sci Rep. 7(1):156

2. Liu J, Yang B, Zhou P, Kong Y, Zhu G, Li W, Wang Y*, Li S (2017) Nicotinamide adenine dinucleotide suppresses epileptogenesis at early stage. Sci Rep. 7:7321

3. Cheng L, Duan B, Huang T, Zhang Y, Chen Y, Britz O, Garcia-Campmany L, Ren X, Vong L, Lowell BB, Goulding M, Wang Y *, Ma Q* (2017) Identification of spinal circuits required to transmit touch-evoked dynamic mechanical pain. Nature Neuroscience, 26(2):804-817

4. Zhang Y, Huang Y, Wang GX, Wang X*, Wang Y* (2017) 17-beta-Estradiol enhances GIRK1-mediated inwardly rectifying potassium currents and GIRK1 expression, thus reduces neuronal excitability. J Neurol Sci. 375:335-341

5. Chen B, Wang G, Li W, Liu W, Lin R, Tao J, Jiang M, Chen L*, Wang Y* (2017) Memantine Attenuates Cell Apoptosis by Suppressing the Calpain-Caspase-3 Pathway in an Experimental Model of Ischemic Stroke. Exp Cell Res. 351(2):163-172

6. Zhang Y, Huang Y, Liu X, Wang GX, Wang X*, Wang Y* (2015) Estrogen suppresses epileptiform activity via enhancing Kv4.2 mediated transient outward potassium currents in primary hippocampal neurons. Int J Mol Med, 36:865-872.

7. Wang G, Shi Y, Jing X, Leak RK, Hu X, Wu Y, Pu H, Li WW, Tang B, Wang Y, Gao Y, Zheng P, Bennett MVL*, Chen J* (2015) HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3β/PTEN/Akt axis. PNAS, 112(9):2853-2858.

8. Chen B, Wang Y* (2015) Cofilin rod formation in neurons impairs neuronal structure and function. CNS Neurol Disord-DT. 14(4):554-560.

9. Duan B, Cheng L, Bourane S, Britz O, Padilla C, Garcia-Campmany L, Krashes M, Knowlton W, Velasquez T, Ren X, Ross S, Lowell BB, Wang Y, Goulding M*, Ma Q* (2014) Intersectional Genetic Dissection of a Spinal Microcircuit That Transmits and Gates Mechanical Pain. Cell, 159(6):1417-32

10. Wan L, Liu X, Wu Z, Ren W, Kong S, AbouDargham R, Cheng L*, Wang Y* (2014) Activation of extrasynaptic GABAA receptors inhibited cyclothiazide induced epileptiform activities in hippocampal CA1 neurons. Neurosci Bull, 30(5): 866-876

11. Kong S, Cheng Z, Liu J, Wang Y* (2014) Down-regulated GABA and BDNF-TrkB pathway in chronic cyclothiazide seizure model. Neural Plasticity, Volume 2014, Article ID 310146.

Scientific focus :

Faculty Member