Despite vast effort, no major gene has yet emerged as contributing to the seizure/epilepsy phenotypes from these previous studies. Many reasons could explain this fact; however, primary among all is likely to be the multigenic nature of the phenotypes and the complex gene-gene and gene-environment interactions, which also help determine them. Added to this complexity are many environmental variables which are essentially unknown and therefore uncontrolled. Animal investigations have pointed out this limitation several times (Frankel et al., 1994). Thus, environmental factors shown to influence experimental seizures induced by nonpharmacological means (Todorova et al., 1999) are likely also relevant in seizure paradigms based on the action of chemoconvulsant drugs. The interaction between genes is also a major factor that must be addressed. Frankel et al. showed that a RIS derived from the cross of two nonepileptic strains (SWR/J × C57L/J) led to the SWXL-4 epileptic strain, which exhibits tonic-clonic and generalized seizures (Frankel et al., 1994). More recently, two studies have reinforced this point of view. In the stargazer mouse, which is mutated on Cacng2 (Letts et al., 1998), a targeted mutation on Cacng4 increases the SWD (spike and wave discharge) activity in the stargazer double mutant compared to “wild-type” stargazer, i.e., mutated only on Cacng2 (Letts et al., 2005). Frankel et al. have also shown the impact of interaction between genes on spike SWD activity (Frankel et al., 2005). The authors isolated SWD activity in a C3H/He substrain background; however, in a C57BL/6J × C3H/HeJ F1 population, no SWD activity was observed. Testing of the backcross population (C57BL/6J × C3H/HeJ F1) × C3H/HeJ showed there was an heterosis effect, i.e., the backcross population has greater SWD activity than the C3H/HeJ strain (Frankel et al., 2005). Surprisingly, a C57BL/6J determinant was found to be involved in the SWD expression. Since this strain is devoid of SWD activity, only a combination of allelic forms from C3H/HeJ and C57BL/6J could explain this phenomenon.
As can be seen in Table 1, the involvement of distal chromosome 1 is recurrent throughout the different mapping studies presented here. Although it is possible that different genes at this locus mediate the seizure phenotypes elicited by the various chemoconvulsants studied, the simplest hypothesis is that there is a common gene of fundamental importance whose variation influences seizure expression induced by diverse pharmacological compounds. Kosobud et al. have suggested previously the possibility of a general factor for a multidrug susceptibility (Kosobud and Crabbe, 1990). Based upon information available in publically accessible genome databases (Ferraro et al., 2004), at least three genes at this locus are obvious candidates from a purely biological perspective. These include Kcnj9, Kcnj10, and Atpa2 with Kcnj10 being the most compelling candidate. Kcnj9, a potassium inwardly-rectifying channel, has been associated with Type 2 diabetes in Pima Indians (Farook et al., 2002); however, there are no known neurological phenotypes linked to this gene. In mice, animals −/− for Kcnj9 have no particular phenotype; however, this study suggests an indirect involvement of Kcnj9 in seizures because mice −/− for Kcnj9 and Kcnj6 have lethal spontaneous seizures between 2 and 8 months of age (Torrecilla et al., 2002). Atp1a2, an ATP-linked potassium ion channel gene, has been knocked out in the mouse, but −/− mice die at birth (Ikeda et al., 2003) and it is not clear if alterations in neuronal excitability are involved. Initial studies of this gene in patients with epilepsy have been negative, however, suggesting it is not a major susceptibility factor (Buono et al., 2000; Lohoff et al., 2005). The inward-rectifying potassium ion channel gene Kcnj10 has been elevated in status as a candidate due to several factors. First, a nonsynonymous single nucleotide polymorphism (SNP) distinguishes C57-derived strains from DBA/2J (and most other common inbred strains) (Ferraro et al., 2004). The SNP predicts an amino acid variation (Thr262Ser) in the multifunctional intracellular C-terminus of the protein (Ferraro et al., 2004). Studies in humans have shown that a KCNJ10 SNP (Arg271Pro) near the one found in the mouse gene is associated with common forms of epilepsy (Buono et al., 2004, Lenzen et al., 2005), thus indirectly supporting a role for this gene in the mouse model. Homozygous Kcnj10 knockout mice are not viable past weaning; thus, it has not been possible to assess seizure activity or thresholds in this model. However, studies early in life note degeneration in the inner ear and deafness (Rozengurt et al., 2003). Finally, a recent study has shown that the protein variations found in humans and mice have no effect on the intrinsic properties of the channel in vitro (Shang et al., 2005). In vivo, however, a role for Kcnj10 or a tightly linked gene in seizure susceptibility has been documented by using a BAC transgenesis strategy (Ferraro et al., 2007).
Kcnj10 has been suggested not only for these previous traits. It has been described as being potentially involved in pentobarbital withdrawal (Buck et al., 1999), maximal electroshock seizure threshold (Ferraro et al., 2001) and in ethanol withdrawal severity (Buck et al., 2002). This potential multiple involvement in models of neuronal hyperexcitability underlines the interactions between several processes and seems to confer a central role upon the distal part of chromosome 1 (and so Kcnj10) in all of these pathways, either at the starting point or at the end. If this general involvement of Kcnj10 is confirmed, and a common genetic basis for chemoconvulsant sensitivity is documented, it may greatly facilitate the diagnosis and treatment of epilepsy in humans. Further studies in both mice and men are warranted to continue to evaluate this hypothesis.