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dc.contributor.authorBrunal, Alyssa A.en
dc.contributor.authorClark, Kareem C.en
dc.contributor.authorMa, Manxiuen
dc.contributor.authorWoods, Ian G.en
dc.contributor.authorPan, Y. Alberten
dc.date.accessioned2021-01-12T14:27:32Zen
dc.date.available2021-01-12T14:27:32Zen
dc.date.issued2021-01-11en
dc.identifier.urihttp://hdl.handle.net/10919/101851en
dc.description.abstractConnexins are transmembrane proteins that form hemichannels allowing the exchange of molecules between the extracellular space and the 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 within 30min. This Cx36 reduction persists after 1-h of recovery but recovered after 3–6 h. 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 regionspecific susceptibility to neuronal hyperactivity, while neuronal hyperactivity-induced downregulation of Cx36 may increase the risk of future epileptic events.en
dc.description.sponsorshipThis work was supported by funding from the Commonwealth Research Commercialization Fund (ER14S-001-LS to YP) and Virginia Tech.en
dc.language.isoen_USen
dc.publisherFrontiers Mediaen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectMAP-mappingen
dc.subjectepilepsyen
dc.subjectseizureen
dc.subjectgap junction (connexin)en
dc.subjectbrain mappingen
dc.titleEffects of Constitutive and Acute Connexin 36 Deficiency on Brain-Wide Susceptibility to PTZ-Induced Neuronal Hyperactivityen
dc.typeArticle - Refereeden
dc.title.serialFrontiers in Molecular Neuroscienceen
dc.identifier.doihttps://doi.org/10.3389/fnmol.2020.587978en
dc.identifier.volume13en


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Attribution 4.0 International
License: Attribution 4.0 International