Double trouble? Potential for hyperexcitability following both channelopathic up- and downregulation of Ih in epilepsy

Abstract

Studies of pathological ion channel regulation as an underlying mechanism of epilepsy have revealed alterations in the h-current in several animal models. While earlier reports indicate that downregulation of the h-current is pro-excitatory on the single neuron level, we found an upregulation of Ih in hyperexcitable CA1 pyramidal neuron dendrites following experimental febrile seizures. In addition, in several CA1 pyramidal neuron computational models of different complexity, h-current upregulation has been shown to lead to pro-excitable effects. This focused review examines the complex impact of altered h-current on neuronal resting membrane potential (RMP) and input resistance (Rin), as well as reported interactions with other ionic conductances.

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

“…It should be noted that opposite results have also been reported, such as upregulation of I h in hyperexcitable CA1 pyramidal neurons following febrile seizures (Chen et al, 2001;Dyhrfjeld-Johnsen et al, 2009). I h may therefore be antiepileptogenic in some settings when enhanced, and in others when depressed (Peng et al, 2010).…”

“…Widely expressed in neurons, HCN channels have important functions such as the modulation of excitability and rhythmicity, signal integration, and plasticity (I h current) (Pape, 1996;Robinson and Siegelbaum, 2003;Biel et al, 2009). Because of their role in neuronal excitability, defective HCN1/HCN2 channels, the HCN isoforms expressed in distal dendrites of pyramidal cells in the hippocampus and neocortex (Notomi and Shigemoto, 2004), are considered potential contributors to pathological firing in specific forms of epilepsy (Bender and Baram, 2008;Dubé et al, 2009;Dyhrfjeld-Johnsen et al, 2009;Reid et al, 2009;Lewis and Chetkovich, 2011). Evidence supporting a link between functional alteration of HCN channels and epileptogenesis has resulted typically from analysis of Hcn1 and Hcn2 knock-out mouse models.…”

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

“…The changes described above, a more hyperpolarized V m and an increased R in, make it difficult to predict the net effect on intrinsic excitability of L5 neurons (Dyhrfjeld-Johnsen et al 2009). We therefore examined the relationship between somatic current injection and AP firing in neurons from sham-operated and lesioned animals.…”

High-conductance states and A-type K+ channels are potential regulators of the conductance-current balance triggered by HCN channels

“…However, unlike most channels that mediate inward currents, HCN channels are activated by hyperpolarization. As a direct consequence of this, activation of these channels would resist changes in membrane potential, thereby reducing the input resistance of the neuron through an overall increase in the membrane conductance (Dyhrfjeld-Johnsen et al 2009;Gasparini and DiFrancesco 1997;He et al 2014;Hutcheon and Yarom 2000;Magee 1998;Migliore and Migliore 2012;Narayanan and Johnston 2008;Pape 1996;Robinson and Siegelbaum 2003;Santoro and Baram 2003;Shah 2014). Together, the expression of HCN channels acts to increase neuronal excitability by depolarizing the membrane and taking the neuron closer to firing, and simultaneously acts to reduce neuronal gain through the consequent increase in membrane conductance.…”

“…Together, the expression of HCN channels acts to increase neuronal excitability by depolarizing the membrane and taking the neuron closer to firing, and simultaneously acts to reduce neuronal gain through the consequent increase in membrane conductance. Such dichotomous impact of HCN channels on neuronal excitability and the underlying balance between the HCN conductance and the h current have been at the center of a wide-ranging debate on the regenerative vs. restorative roles of these channels in regulating neuronal physiology (Breton and Stuart 2009;Chen et al 2001;Dyhrfjeld-Johnsen et al 2009;Fan et al 2005;George et al 2009;Kim et al 2012;Lippert and Booth 2009;Magee 1998;Migliore and Migliore 2012;Narayanan and Johnston 2007;Noam et al 2011;Pavlov et al 2011;Rosenkranz and Johnston 2006;Santoro and Baram 2003). The analysis of whether HCN channel expression leads to restorative or regenerative effects is central to ascribing homeostatic vs. excitotoxic roles for changes in these channels under several physiological and pathophysiological conditions (Brager et al 2012;Brager and Johnston 2007;DyhrfjeldJohnsen et al 2009;Fan et al 2005;Jung et al 2007;Kole et al 2007;Lerche et al 2013;Narayanan and Johnston 2007;Santoro and Baram 2003;Shah 2014;Shah et al 2004;van Welie et al 2004).…”