title: Neuronal carbonic anhydrase VII provides GABAergic excitatory drive to exacerbate febrile seizures.
abstract: Brain carbonic anhydrases (CAs) are known to modulate neuronal signalling. Using a novel CA VII (Car7) knockout (KO) mouse as well as a CA II (Car2) KO and a CA II/VII double KO, we show that mature hippocampal pyramidal neurons are endowed with two cytosolic isoforms. CA VII is predominantly expressed by neurons starting around postnatal day 10 (P10). The ubiquitous isoform II is expressed in neurons at P20. Both isoforms enhance bicarbonate-driven GABAergic excitation during intense GABAA-receptor activation. P13-14 CA VII KO mice show behavioural manifestations atypical of experimental febrile seizures (eFS) and a complete absence of electrographic seizures. A low dose of diazepam promotes eFS in P13-P14 rat pups, whereas seizures are blocked at higher concentrations that suppress breathing. Thus, the respiratory alkalosis-dependent eFS are exacerbated by GABAergic excitation. We found that CA VII mRNA is expressed in the human cerebral cortex before the age when febrile seizures (FS) occur in children. Our data indicate that CA VII is a key molecule in age-dependent neuronal pH regulation with consequent effects on generation of FS.
authors.affiliation: Department of Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Eva
authors.initials: E
authors.lastname: Ruusuvuori
authors.forename: Antje K
authors.initials: AK
authors.lastname: Huebner
authors.forename: Ilya
authors.initials: I
authors.lastname: Kirilkin
authors.forename: Alexey Y
authors.initials: AY
authors.lastname: Yukin
authors.forename: Peter
authors.initials: P
authors.lastname: Blaesse
authors.forename: Mohamed
authors.initials: M
authors.lastname: Helmy
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kang
authors.forename: Malek
authors.initials: M
authors.lastname: El Muayed
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Hennings
authors.forename: Juha
authors.initials: J
authors.lastname: Voipio
authors.forename: Nenad
authors.initials: N
authors.lastname: Šestan
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hübner
authors.forename: Kai
authors.initials: K
authors.lastname: Kaila
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D024402:Carbonic Anhydrase II / Q000235:genetics / Q000378:metabolism*; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology* / Q000378:metabolism; D003975:Diazepam / Q000633:toxicity; D004569:Electroencephalography; D005453:Fluorescence; D059330:GABAergic Neurons / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D003294:Seizures, Febrile / Q000139:chemically induced / Q000201:enzymology* / Q000378:metabolism
chemical_list: D024402:Carbonic Anhydrase II; D002256:Carbonic Anhydrases; C584060:carbonic anhydrase 7, mouse; D003975:Diazepam