title: Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice?
abstract: BACKGROUND
  Brain ischemia is known to include neuronal cell death and persisting neurological deficits. A lack of oxygen and glucose are considered to be key mediators of ischemic neurodegeneration while the exact mechanisms are yet unclear. In former studies the expression of two different two-pore domain potassium (K2P) channels (TASK1, TREK1) were shown to ameliorate neuronal damage due to cerebral ischemia. In neurons, TASK channels carrying hyperpolarizing K+ leak currents, and the pacemaker channel HCN2, carrying depolarizing Ih, stabilize the membrane potential by a mutual functional interaction. It is assumed that this ionic interplay between TASK and HCN2 channels enhances the resistance of neurons to insults accompanied by extracellular pH shifts.
  
  
  METHODS
  In C57Bl/6 (wildtype, WT), hcn2+/+ and hcn2-/- mice we used an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of HCN2 in stroke formation. Subsequent analyses comprise behavioural tests and hcn2 gene expression assays.
  
  
  RESULTS
  After 60 min of tMCAO induction in WT mice, we collected tissue samples at 6, 12, and 24 h after reperfusion. In the infarcted neocortex, hcn2 expression analyses revealed a nominal peak of hcn2 expression 6 h after reperfusion with a tendency towards lower expression levels with longer reperfusion times. Hcn2 gene expression levels in infarcted basal ganglia did not change after 6 h and 12 h. Only at 24 h after reperfusion, hcn2 expression significantly decreases by ~55%. However, 30 min of tMCAO in hcn2-/- as well as hcn2+/+ littermates induced similar infarct volumes. Behavioural tests for global neurological function (Bederson score) and motor function/coordination (grip test) were performed at day 1 after surgery. Again, we found no differences between the groups.
  
  
  CONCLUSIONS
  Here, we hypothesized that the absence of HCN2, an important functional counter player of TASK channels, affects neuronal survival during stroke-induced tissue damage. However, together with a former study on TASK3 these results implicate that both TASK3 and HCN2 which were supposed to be neuroprotective due to their pH-dependency, do not influence ischemic neurodegeneration during stroke in the tMCAO model.
authors.affiliation: Department of Neurology, and Institute of Physiology, Neuropathophysiology, Albert-Schweitzer-Campus 1, Westfälische Wilhelms University, 48149 Münster, Germany.|Department of Neurology, ICB, Mendelstr. 7, 48149 Münster, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Ehling
authors.affiliation: Department of Neurology, University Clinic Würzburg, Josef-Schneider-Str. 11, Würzburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Göb
authors.affiliation: Department of Neurology, Albert-Schweitzer-Campus 1, Westfälische Wilhelms University, Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.affiliation: Institute of Physiology I, Westfälische Wilhelms University, Robert-Koch-Str. 27a, Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Budde
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander Universität Erlangen-Nürnberg, Fahrstr. 17, Erlangen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.affiliation: Department of Neurology, University Clinic Würzburg, Josef-Schneider-Str. 11, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.affiliation: Department of Neurology, and Institute of Physiology, Neuropathophysiology, Albert-Schweitzer-Campus 1, Westfälische Wilhelms University, 48149 Münster, Germany.|Department of Neurology, Albert-Schweitzer-Campus 1, Westfälische Wilhelms University, Münster, Germany.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth