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Keywords:

  • Mapping;
  • QTL;
  • Kcnj10;
  • Mouse;
  • Kainic acid;
  • Pentylenetetrazol;
  • Beta-carbolines;
  • DMCM;
  • Beta;
  • CCM

Abstract

  1. Top of page
  2. Abstract
  3. Kainic acid mapping studies
  4. Pentylenetetrazol mapping studies
  5. ß-carboline mapping studies
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES

Summary:  Despite the efforts employed, understanding the genetic architecture underlying epilepsy remains difficult. To reach this aim, convulsive epilepsies are classically modeled in mice, where genetic studies are less constricting than in humans. Pharmacogenetic approaches are one major source of investigation where kainic acid, pentylenetetrazol, and the ß-carboline family represent compounds that are used extensively. Several quantitative trait loci (QTLs) influencing the convulsant effects of these drugs have been mapped using either recombinant inbred strains (RIS) or segregating F2 populations (or both). In our laboratory, we have recently mapped two QTLs for methyl 6, 7-dimethoxy-4-ethyl-ß-carboline-3-carboxylate (DMCM), and seizure response using an F2 method. One is located on the distal part of Chromosome 1, a region implicated in a number of other studies. Here, we address the general importance of this chromosomal fragment for influencing seizure susceptibility.

It is well known that idiopathic epilepsies have a complex genetic architecture (Bate and Gardiner, 1999). Many genetic studies on humans have revealed a collection of genes involved in different forms of epilepsy (for review, see Crunelli and Leresche, 2002). In general, each study has reported distinct loci and findings have been difficult to replicate between studies. For example, the 5p15 and 5q14-q22 human regions have been shown to be involved in several idiopathic generalized epilepsies (IGEs) (Durner et al., 2001) but this association has not been found in work with other epileptic families (Windemuth et al., 2002).

Considering the difficulties involved in conducting genetic experiments in humans, including ethical issues, animal models play a major role in studying epilepsy. Seizures can be induced in rodents using different types of pharmacologic and pharmacogenetic investigations and several convulsant drugs have been studied extensively. Among these are kainic acid (KA), a glutamate agonist, pentylenetetrazol (PTZ) a GABA antagonist and the ß-carboline compounds, methyl 6, 7-dimethoxy-4-ethyl-ß-carboline-3-carboxylate (DMCM) and methyl ß-carboline-3-carboxylate (ß-CCM), GABA-A inverse agonists.

Mapping studies in mice have made extensive use of recombinant inbred strains (RIS) and segregating F2 populations. The RIS are a set of different inbred strains each representing an individual F2 genome derived from two progenitor strains. For a given trait of interest, linkage principles are used to compare the subset of RIS carrying one allelic form with the other subset carrying the other form. They are not created especially for one study but several sets of RIS with different progenitor strains are available to the scientific community (http://www.informatics.jax.org/searches/riset_form.shtml). RIS are generally used to detect chromosomal regions involved in a phenotype with a monogenic inheritance or for major genes involved in a multigenic phenotype. Since RIS genotypes are available in free-access through web sources, the mapping analysis is possible without any PCR step (Bailey, 1971; Taylor, 1978). Segregating populations such as F2 are also derived from intercrosses between two inbred strains but in contrast to RIS, individual genetically-unique F2 progeny are generated and tested for the phenotype of interest. A polymerase chain reaction (PCR) or a sequencing approach is then undertaken to detect linkages between a marker/gene and the phenotype (Ferraro et al., 1998).

Mapping studies for KA-, PTZ-, DMCM-, and ß-CCM-induced seizures have led to the identification of several chromosomal regions that may harbor genes influencing these diverse seizure paradigms. Of the numerous loci detected, those from the distal part of the chromosome 1 (∼85–100 cM) were found significant and highly significant most regularly (Ferraro et al., 1997; Ferraro et al., 1999). Other seizure traits and seizure-related traits are also influenced by a gene or genes in this region (Buck et al., 1999; Ferraro et al., 2001; Buck et al., 2002). This seizure susceptibility “hot spot” contains several compelling candidate genes and particularly one coding for a unique potassium channel, Kcnj10. Recently we have done a mapping study for DMCM-induced seizures. Here again the same region was noted to contribute significant effects (unpublished data). The purpose of the present work aims to compare the different mapping studies for these convulsants with their convergence toward the Kcnj10 hypothesis on Chromosome 1.

Kainic acid mapping studies

  1. Top of page
  2. Abstract
  3. Kainic acid mapping studies
  4. Pentylenetetrazol mapping studies
  5. ß-carboline mapping studies
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES

KA is an agonist of the glutamatergic system but also a convulsant that elicits a phenotype that mimics many features of the human temporal lobe epilepsy (Nadler, 1981; Ben-Ari, 1985). Genetic mapping on F2 progeny (Ferraro et al., 1997) derived from two strains, C57BL/6J and DBA/2J, known to have a marked difference in their seizure response to KA (Ferraro et al., 1995) revealed seven QTLs: Szs1 (Seizure susceptibility 1), Szv1 (Seizure severity 1), Szs2, Szs3, Szs4, Szv2 and Szv3 (Ferraro et al., 1997). Of these QTLs, Szs1 on distal chromosome 1 carried the greatest effect. All data for KA as well as other convulsants are summarized in Table 1.

Table 1. Localization of the chemoconvulsant induced seizure susceptibility QTLs. Positions are shown by a red triangleThumbnail image of

Pentylenetetrazol mapping studies

  1. Top of page
  2. Abstract
  3. Kainic acid mapping studies
  4. Pentylenetetrazol mapping studies
  5. ß-carboline mapping studies
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES

PTZ is an antagonist of GABA-A receptors (Ramanjaneyulu and Ticku, 1984) with convulsant action variable according to the strain employed (Kosobud and Crabbe, 1990). Four QTLs have been identified on chromosomes 1, 4, and 5 (Ferraro et al., 1999; Ferraro et al., 1998). Three of the QTLs overlap with those described in KA-induced seizure susceptibility (Ferraro et al., 1997), suggesting an involvement larger than a specific interaction with PTZ (Ferraro et al., 1999). As in the KA screen, the distal chromosome 1 effect was the most powerful detected in the PTZ screen. Subsequently, two other QTLs have been described in C57BL/6J and DBA/2J mice (Wakana et al., 2000), the most significant being located on chromosome 2, Ptz1a and Ptz1b (pentylenetetrazol-induced seizure susceptibility 1), and a more minor influence located on chromosome 7. Interestingly, there was no signal detected on chromosome 1. The existence of discrepancies between results is often due to the employment of different progenitor mouse strains for the experiments. But in the present case, the authors have used the same methods and strains (RIS, F2, and BXD populations). These results may be explained by environmental factors (Crabbe et al., 1999), including possible subtle protocol variations (Todorova et al., 2006). Determination of expression QTLs throughout the genome using backcross panels involving C3H and DBA mice showed that there was no overlap between PTZ-induced gene expression changes and PTZ seizure susceptibility QTLs (Wakana et al., 2000).

ß-carboline mapping studies

  1. Top of page
  2. Abstract
  3. Kainic acid mapping studies
  4. Pentylenetetrazol mapping studies
  5. ß-carboline mapping studies
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES

DMCM and ß-CCM are full inverse agonists of GA-BA-A receptors and thus are characteristic ß-carbolines with convulsant activity in vivo (Prado de Carvalho et al., 1984). Quantitative genetic investigations have shown the complexity of the genetic mechanism underlying these convulsions (Kosobud and Crabbe, 1990; Martin et al., 1991; Martin et al., 1994). Several mapping studies have been run for ß-CCM responses involving different mouse strains (Clement et al., 1996; Gershenfeld et al., 1999; Martin et al., 1995; Mathis et al., 1995). Recently, we performed genetic mapping for DMCM-induced seizure susceptibility. We used an F2 segregating population from two mouse lines bidirectionally selected for their response to ß-carboline-induced seizures (Chapouthier et al., 1998). Two QTLs have been identified, located on the distal part of chromosome 1 and on chromosome 5 (unpublished data). The significant chromosome 1 segment includes the Kcnj10 locus. A genotyping study has shown that the susceptible line and the resistant line that we have used in our study carry, respectively, a DBA/2 allele and a C57BL/6J allele, for Kcnj10. This last result supports the Kcnj10 involvement hypothesis. It can be noticed that each study–including ours—has identified unique chromosomal regions except for the distal part of the chromosome 4, revealed twice (Martin et al., 1995; Gershenfeld et al., 1999). The divergence among the results is certainly due to the fact that genetic models and mouse strains used as well as environmental situations in each experiment were different.

DISCUSSION

  1. Top of page
  2. Abstract
  3. Kainic acid mapping studies
  4. Pentylenetetrazol mapping studies
  5. ß-carboline mapping studies
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES

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.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Kainic acid mapping studies
  4. Pentylenetetrazol mapping studies
  5. ß-carboline mapping studies
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES

Acknowledgments:  This study was supported by the Region Centre, the Ligue Française Contre l'Epilepsie, The Pfizer Laboratories, the Centre National de la Recherche Scientifique and the Université d'Orléans.

REFERENCES

  1. Top of page
  2. Abstract
  3. Kainic acid mapping studies
  4. Pentylenetetrazol mapping studies
  5. ß-carboline mapping studies
  6. DISCUSSION
  7. Acknowledgments
  8. REFERENCES
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