Effects of Constitutive and Acute Connexin 36 Deficiency on Brain-Wide Susceptibility to PTZ-Induced Neuronal Hyperactivity
| dc.contributor.author | Brunal, Alyssa A. | en |
| dc.contributor.author | Clark, Kareem C. | en |
| dc.contributor.author | Ma, Manxiu | en |
| dc.contributor.author | Woods, Ian G. | en |
| dc.contributor.author | Pan, Yuchin Albert | en |
| dc.date.accessioned | 2021-01-12T14:27:32Z | en |
| dc.date.available | 2021-01-12T14:27:32Z | en |
| dc.date.issued | 2021-01-11 | en |
| dc.description.abstract | Connexins 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.sponsorship | This work was supported by funding from the Commonwealth Research Commercialization Fund (ER14S-001-LS to YP) and Virginia Tech. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.doi | https://doi.org/10.3389/fnmol.2020.587978 | en |
| dc.identifier.uri | http://hdl.handle.net/10919/101851 | en |
| dc.identifier.volume | 13 | en |
| dc.language.iso | en | en |
| dc.publisher | Frontiers | en |
| dc.rights | Attribution 4.0 International | en |
| dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en |
| dc.subject | MAP-mapping | en |
| dc.subject | epilepsy | en |
| dc.subject | seizure | en |
| dc.subject | gap junction (connexin) | en |
| dc.subject | brain mapping | en |
| dc.title | Effects of Constitutive and Acute Connexin 36 Deficiency on Brain-Wide Susceptibility to PTZ-Induced Neuronal Hyperactivity | en |
| dc.title.serial | Frontiers in Molecular Neuroscience | en |
| dc.type | Article - Refereed | en |
| dc.type.dcmitype | Text | en |