Developmental Seizure Susceptibility of Kv1.1 Potassium Channel Knockout Mice

Abstract

Potassium channels play a critical role in limiting neuronal excitability. Mutations in certain voltage-gated potassium channels have been associated with hyperexcitable phenotypes in both humans and animals. However, only recently have mutations in potassium channel genes (i.e. KCNQ2 and KCNQ3) been discovered in a human epilepsy, benign familial neonatal convulsions. Recently, it has been reported that mice lacking the voltage-gated Shaker-like potassium channel Kv1.1 α-subunit develop recurrent spontaneous seizures early in postnatal development. The clinical relevance of the Kv1.1 knockout mouse has been underscored by a recent report of epilepsy occurring in a family affected by mutations in the KCNA1 locus (the human homologue of Kv1.1) which typically cause episodic ataxia and myokymia. Here we summarize preliminary studies characterizing the developmental changes in seizure susceptibility and neuronal activation in the three genotypes of Kv1.1 mice (–/–, +/–, +/+). Using behavioral and immediate-early gene indicators of regional brain excitability, we have found that a seizure-sensitive predisposition exists in Kv1.1 –/– animals at a very young age (P10), before either spontaneous seizure activity or changes in c-fos mRNA expression can be demonstrated. Kv1.1 +/– mice, although behaviorally indistinguishable from wild types, also have an increased susceptibility to seizures at a similar early age. The Kv1.1 knockout mouse possesses many features desirable in a developmental animal epilepsy model and represents a clinically relevant model of early-onset epilepsies.

Physiological bases of the K+ and the glutamate/GABA hypotheses of epilepsy

“…Therefore, gain-of-function of Na + channels (for a comprehensive review, see Eijkelkamp et al, 2012) and/or loss-of-function of K + channels (for a comprehensive review, see D’Adamo et al, 2013) have proepileptic effects in most cases. Some examples include gain-of-function of voltage-gated Na + (Nav) channels Nav1.2/1.6 (responsible for action potential generation and propagation) (Sugawara et al, 2001), Nav1.3 (responsible for dendritic postsynaptic potentials propagation) (Estacion et al, 2010; Holland et al, 2008), and loss-of-function of voltage-gated K + (Kv) channels Kv1.1/1.2 (responsible for action potentials propagation and vesicles release) (Brew et al, 2007; Rho et al, 1999), Kv2.1/8.2 (responsible for dendritic postsynaptic potentials propagation) (Jorge et al, 2011), Kv4.2 (responsible for backpropagating action potentials in dendrites) (Barnwell et al, 2009; Bernard et al, 2004), Kv7.2/7.3 (required for repolarization of AIS) (Peters et al, 2005). There are notable exceptions to this rule, as the effect of these changes is reversed when they target inhibitory neurons.…”

Postnatal development of A-type and Kv1- and Kv2-mediated potassium channel currents in neocortical pyramidal neurons

“…These properties may limit pyramidal cell activity at ages prior to the mature expression of GABA-mediated synaptic inhibition, which begins at ϳP8 (Agmon and O'Dowd 1992). Interestingly, in Kv1.1 knockout mice, seizure susceptibility manifests at ϳ2 wk of age (Rho et al 1999). Several aspects of somatosensory cortical function exhibit plasticity and are sensitive to activity during critical periods of development (Feldman et al 1999;Hentsch 2005).…”

Kv1.1 null mice have enlarged hippocampus and ventral cortex

“…The Kv1.1 null mice are epileptic on all genetic backgrounds tested including 129/SvJ, N:NIH-BC, C57BL/6J, C3HeB/FeJ, Swiss Black and hybrids thereof, but has not previously been reported to have excessive brain growth [8]. Investigation of brain morphology in 3 months old Kv1.1 null mice on 129/SvJ × Swiss black hybrid background revealed only the typical effects of seizures in the hippocampus: neuronal loss and mossy fiber sprouting [9]. Hence, we here report for the first time that Kv1.1.null mice can display excessive brain growth.…”