title: An impaired neocortical Ih is associated with enhanced excitability and absence epilepsy.
abstract: Neuronal subthreshold excitability and firing behaviour are markedly influenced by the activation and deactivation of the somato-dendritic hyperpolarization-activated cation current (Ih). Here, we evaluated possible contributions of Ih to hyperexcitability in an animal model of absence seizures (WAG/Rij rats). We investigated pyramidal neurons of the somatosensory neocortex, the site of generation of spike-wave discharges. Ih-mediated functions in neurons from WAG/Rij rats, Wistar rats (sharing the same genetic background with WAG/Rij, but less epilepsy-prone) and ACI rats (an inbred strain, virtually free of seizures) were compared. We complemented whole-cell recordings from layer 2-3 pyramidal neurons with immunohistochemistry, Western blot and RT-PCR analysis of the h-channel subunits HCN1-4. The fast component of Ih activation in WAG/Rij neurons was significantly reduced (50% reduction in the h-current density) and four times slower than in neurons from nonepileptic Wistar or ACI rats. The results showing decreases in currents corresponded to a 34% reduction in HCN1 protein in the WAG/Rij compared to the Wistar neocortex, but HCN1 mRNA showed stable expression. The other three Ih subunit mRNAs and proteins (HCN2-4) were not affected. The alterations in Ih magnitude and kinetics of gating in WAG/Rij neurons may contribute to augmented excitatory postsynaptic potentials, the increase in their temporal summation and the facilitation of burst firing of these neurons because each of these effects could be mimicked by the selective Ih antagonist ZD 7288. We suggest that the deficit in Ih-mediated functions may contribute to the development and onset of spontaneously occurring hyperexcitability in a rat model of absence seizures.
authors.affiliation: Department of Neurology, University Rostock, Gehlsheimer Strasse 20, 18147 Rostock, Germany. ulf.strauss@med.uni-rostock.de
authors.forename: Ulf
authors.initials: U
authors.lastname: Strauss
authors.forename: Maarten H P
authors.initials: MH
authors.lastname: Kole
authors.forename: Anja U
authors.initials: AU
authors.lastname: Bräuer
authors.forename: Jens
authors.initials: J
authors.lastname: Pahnke
authors.forename: Rika
authors.initials: R
authors.lastname: Bajorat
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.forename: Robert
authors.initials: R
authors.lastname: Nitsch
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Deisz
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D017097:Electric Impedance; D004832:Epilepsy, Absence / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D019579:Neocortex / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D015221:Potassium Channels / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000503:physiopathology*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013045:Species Specificity
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007473:Ion Channels; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D011743:Pyrimidines; D012333:RNA, Messenger; C082246:ICI D2788; D015763:2-Amino-5-phosphonovalerate