Dynamic expression of CX36 protein in kainic acid kindling induced epilepsy

Wu, Xuemei; Wang, Guangliang; Hao, Xiaosheng; Feng, Jiachun

doi:10.1515/tnsci-2017-0007

Cited by 10 publications

(9 citation statements)

References 28 publications

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“…Gap junction that promotes synchronous firing of neurons was also suggested to play an important role in the generation of seizures. Its constructive protein Cx36 was found significantly increased hours after KA administration, then decreased days later (Wu et al, 2017 ). The accumulating evidence indicates that not only glutamate receptors, but also other various mechanisms were involved in KA-induced hyperexcitability and epileptogenesis.…”

Section: Discussionmentioning

confidence: 99%

Compensatory Mechanisms Modulate the Neuronal Excitability in a Kainic Acid-Induced Epilepsy Mouse Model

Pan

Chen

Zheng

et al. 2018

Front. Neural Circuits

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Epilepsy is one of the most common neurological disorders affecting millions of people. Due to the complicated and unclear mechanisms of epilepsy, still a significant proportion of epilepsy patients remain poorly controlled. Epilepsy is characterized by convulsive seizures that are caused by increased excitability. In this study, by using kainic acid (KA)-induced epilepsy mice, we investigated the neuronal activities and revealed the neuronal compensatory mechanisms after KA-induced toxic hyperexcitability. The results indicate that both phasic inhibition induced by enhanced inhibitory synaptic activity and tonic inhibition mediated by activated astrocytes participate in the compensatory mechanisms. Compensatory mechanisms were already found in various neuronal disorders and were considered important in protecting nervous system from toxic hyperexcitability. This study hopefully will provide valuable clues in understanding the complex neuronal mechanisms of epilepsy, and exploring potential clinical treatment of the disease.

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Section: Discussionmentioning

confidence: 99%

Compensatory Mechanisms Modulate the Neuronal Excitability in a Kainic Acid-Induced Epilepsy Mouse Model

Pan

Chen

Zheng

et al. 2018

Front. Neural Circuits

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“…In addition, the depletion of ATP during brain ischemia (Sato et al, 1984 ) may cause an increase of [Mg 2+ ] i (Henrich and Buckler, 2008 ). The connection between Mg 2+ deficiency and formation of epileptic seizures is well-established (Randall et al, 1959 ; Hanna, 1961 ; Nuytten et al, 1991 ), and the role of electrical synapses and Cx36 in epilepsy is an important topic of research (Gajda et al, 2005 ; Volman et al, 2011 ; Kohmann et al, 2016 ; Wu et al, 2017 ). Furthermore, brain [Mg 2+ ] i is decreased in patients with Alzheimer's and Parkinson's disease (Durlach, 1990 ; Barbiroli et al, 1999 ), while patients with schizophrenia and traumatic brain injury show increased brain [Mg 2+ ] i (Hinsberger et al, 1997 ).…”

Section: Introductionmentioning

confidence: 99%

Modulation of Connexin-36 Gap Junction Channels by Intracellular pH and Magnesium Ions

et al. 2018

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Connexin-36 (Cx36) protein forms gap junction (GJ) channels in pancreatic beta cells and is also the main Cx isoform forming electrical synapses in the adult mammalian brain. Cx36 GJs can be regulated by intracellular pH (pHi) and cytosolic magnesium ion concentration ([Mg2+]i), which can vary significantly under various physiological and pathological conditions. However, the combined effect and relationship of these two factors over Cx36-dependent coupling have not been previously studied in detail. Our experimental results in HeLa cells expressing Cx36 show that changes in both pHi and [Mg2+]i affect junctional conductance (gj) in an interdependent manner; in other words, intracellular acidification cause increase or decay in gj depending on whether [Mg2+]i is high or low, respectively, and intracellular alkalization cause reduction in gj independently of [Mg2+]i. Our experimental and modelling data support the hypothesis that Cx36 GJ channels contain two separate gating mechanisms, and both are differentially sensitive to changes in pHi and [Mg2+]i. Using recombinant Cx36 we found that two glutamate residues in the N-terminus could be partly responsible for the observed interrelated effect of pHi and [Mg2+]i. Mutation of glutamate at position 8 attenuated the stimulatory effect of intracellular acidification at high [Mg2+]i, while mutation at position 12 and double mutation at both positions reversed stimulatory effect to inhibition. Moreover, Cx36*E8Q lost the initial increase of gj at low [Mg2+]i and double mutation lost the sensitivity to high [Mg2+]i. These results suggest that E8 and E12 are involved in regulation of Cx36 GJ channels by Mg2+ and H+ ions.

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“…To further understand the relationship between Cx36 and hyperactivity, we asked the reciprocal question: how does hyperactivity affect Cx36? Similar to the seizure susceptibility studies, work to identify this relationship has remained conflicting (Laura et al, 2015;Motaghi et al, 2017;Söhl et al, 2000;X. Wu et al, 2017).…”

Section: Ptz Induced Hyperactivity Causes a Regionally-specific Decrementioning

confidence: 99%

“…Previous findings are also mixed regarding how neuronal hyperactivity affects the expression of Cx36. In rodent seizure models and epilepsy patient post-mortem samples, some groups have found that Cx36 expression was increased (Collignon et al, 2006;Laura, Xóchitl, Anne, & Alberto, 2015;X. Wu, Wang, Hao, & Feng, 2017), while others found decreased Cx36 expression (Condorelli, Trovato-Salinaro, Mudo, Mirone, & Belluardo, 2003;Söhl et al, 2000) or no change (Motaghi, Sayyah, Babapour, & Mahdian, 2017).…”

Section: Introductionmentioning

confidence: 99%

Effects of constitutive and acute Connexin 36 deficiency on brain-wide susceptibility to PTZ-induced neuronal hyperactivity

Brunal

Clark

et al. 2020

Preprint

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Connexins are transmembrane proteins that form hemichannels allowing the exchange of molecules between the extracellular space and cell interior. Two hemichannels from adjacent cells dock and form a continuous gap junction pore, thereby permitting direct intercellular communication. Connexin 36 (Cx36), expressed primarily in neurons, is involved in the synchronous activity of neurons and may play a role in aberrant synchronous firing, as seen in seizures. To understand the reciprocal interactions between Cx36 and seizure-like neural activity, we examined three questions: a) does Cx36 deficiency affect seizure susceptibility, b) does seizure-like activity affect Cx36 expression patterns, and c) does acute blockade of Cx36 conductance increase seizure susceptibility. We utilize the zebrafish pentylenetetrazol (PTZ; a GABA(A) receptor antagonist) induced seizure model, taking advantage of the compact size and optical translucency of the larval zebrafish brain to assess how PTZ affects brain-wide neuronal activity and Cx36 protein expression. We exposed wild-type and genetic Cx36-deficient (cx35.5- /-) zebrafish larvae to PTZ and subsequently mapped neuronal activity across the whole brain, using phosphorylated extracellular-signal-regulated kinase (pERK) as a proxy for neuronal activity. We found that cx35.5-/- fish exhibited region-specific susceptibility and resistance to PTZ-induced hyperactivity compared to wild-type controls, suggesting that genetic Cx36 deficiency may affect seizure susceptibility in a region-specific manner. Regions that showed increased PTZ sensitivity include the dorsal telencephalon, which is implicated in human epilepsy, and the lateral hypothalamus, which has been underexplored. We also found that PTZ-induced neuronal hyperactivity resulted in a rapid reduction of Cx36 protein levels. 30 minutes and one-hour exposure to 20 mM PTZ significantly reduced the expression of Cx36. This Cx36 reduction persists after one-hour of recovery but recovered after 3-6 hours. This acute downregulation of Cx36 by PTZ is likely maladaptive, as acute pharmacological blockade of Cx36 by mefloquine results in increased susceptibility to PTZ-induced neuronal hyperactivity. Together, these results demonstrate a reciprocal relationship between Cx36 and seizure-associated neuronal hyperactivity: Cx36 deficiency contributes region-specific susceptibility to neuronal hyperactivity, while neuronal hyperactivity-induced downregulation of Cx36 may increase the risk of future epileptic events.

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Dynamic expression of CX36 protein in kainic acid kindling induced epilepsy

Cited by 10 publications

References 28 publications

Compensatory Mechanisms Modulate the Neuronal Excitability in a Kainic Acid-Induced Epilepsy Mouse Model

Compensatory Mechanisms Modulate the Neuronal Excitability in a Kainic Acid-Induced Epilepsy Mouse Model

Modulation of Connexin-36 Gap Junction Channels by Intracellular pH and Magnesium Ions

Effects of constitutive and acute Connexin 36 deficiency on brain-wide susceptibility to PTZ-induced neuronal hyperactivity

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