Decreased I_H in Hippocampal Area CA1 Pyramidal Neurons after Perinatal Seizure‐inducing Hypoxia

Abstract

Summary:Purpose: The hyperpolarization-activated cation current (I H ) has been proposed to play a role in some forms of epileptogenesis, as it critically regulates synaptic integration and intrinsic excitability of principal limbic neurons and can be pathologically altered after experimentally induced seizures. In hippocampal CA1 pyramidal neurons, I H is functionally decreased after kainate-induced status epilepticus in adult rats but is increased after hyperthermia-induced seizures in immature rat pups. This study aimed to determine whether and how I H may be altered in CA1 pyramidal neurons after seizure-inducing global hypoxia in the neonatal brain.Methods: Seizures were induced in rat pups on postnatal day 10 by 14-to 16-min exposure to 5-7% O 2 . Whole-cell patchclamp recordings were obtained from hippocampal CA1 pyramidal neurons in slices 30 min to 3 days after hypoxia treatment, and from control age-matched littermates. I H was isolated under voltage-clamp by subtracting current responses to hyperpolarizing voltage steps before and during application of the I H blocker ZD 7288 (100 μM).Results: I H was significantly decreased in pyramidal neurons from the hypoxia-treated group compared with controls (p < 0.001; 19 controls; 15 hypoxia). Analyses of tail currents and activation kinetics indicated no statistically significant differences between groups in the voltage dependence or time constants of activation.Conclusions: These data indicate that a single episode of neonatal hypoxia that induces seizures can persistently decrease I H in CA1 pyramidal neurons, raising this as a potential contributing mechanism to epileptogenesis in this setting. Our findings further indicate that the consequences of seizures for I H may depend more on seizure etiology than on maturational stage.

Decreased hyperpolarization-activated currents in layer 5 pyramidal neurons enhances excitability in focal cortical dysplasia

“…Similarly, the spontaneously epileptic WAG/Rij rat exhibits reduced I h associated with increased R in and enhanced synaptic summation (Kole et al 2007;Strauss et al 2004). Perinatal seizures induced by hypoxia are also accompanied by a downregulation of I h (Zhang et al 2006). The present study indicates that reductions in I h associated with increases in cellular excitability and enhanced EPSP summation are found in a nonchemically induced malformation epilepsy model.…”

Inhibition of Ih in Striatal Cholinergic Interneurons Early after Transient Forebrain Ischemia

“…contrary, acute hypoxia caused a disappearance of I h in inspiratory brainstem neurons and dorsal root ganglion neurons (Gao et al, 2006;Mironov et al, 2000). In addition, a partial inhibition of I h , without significant shift of voltage-dependent activation, was observed in hippocampal CA1 pyramidal neurons after neonatal hypoxia in vivo (Zhang et al, 2006a). Different from the above observations, this study revealed that I h in striatal cholinergic interneurons was significantly decreased early (3 h) after transient forebrain ischemia and suggested that the postischemic inhibition of I h might be caused by a negative shift of the voltage dependence of I h activation.…”

“…Thus, regulation of I h may cause profound changes in the membrane excitability of cholinergic interneurons. Several lines of evidence have shown that I h in neurons is very sensitive to ischemic insults (Erdemli and Crunelli, 1998;Gao et al, 2006;Mironov et al, 2000;Ray et al, 2003;Zhang et al, 2006a). However, the role of I h in ischemiainduced neuronal damage remains to be elucidated.…”

Recessive Loss-of-Function Mutation in the Pacemaker HCN2 Channel Causing Increased Neuronal Excitability in a Patient with Idiopathic Generalized Epilepsy

“…Pathological alteration of I h has been shown in several models of seizure-inducing epileptogenesis or increased susceptibility to seizure (Shah et al, 2004;Zhang et al, 2006;Dugladze et al, 2007). Several studies suggest that downregulation of I h can be proepileptogenic (Peng et al, 2010).…”