Genomeenvironment Interactions In Mouse Epilepsy Models

Although this chapter is concerned specifically with transgenic and gene replacement mouse models of epilepsy, a preliminary general discussion of the genome-environment interaction as it relates to mouse seizure phenotypes provides a useful framework for subsequent discussions. Let us begin by considering the commonly (mis)applied distinction between wild-type and mutant mice. If all mice of a given strain exhibited an epilepsy phenotype, and genetic analysis indicated that the phenotype was linked to a single chromosome locus, we would probably feel comfortable referring to that mouse strain as a mutant strain. But then imagine that we moved these mice to a different animal facility (perhaps one with a different temperature, light-dark cycle, or brand of mouse food) and the mice were no longer observed to have seizures. No change in the genome of this mouse strain has occurred, so something in the environment must be responsible for the change in phenotype. Are these mice still mutant? Another example makes a similar point: Multiple studies have now demonstrated that some inbred strains of so-called wild-type mice, even if they never show spontaneous seizures, can be much more easily induced to have seizures than other wild-type strains. Given this information, is it really accurate to imply that the seizure-susceptible and seizure-resistant mouse strains are all equally wild type? Clearly mice are only wild type with respect to a specific genetic locus and according to a specific user-defined assay for the structure or function of that locus in a controlled laboratory environment.

Every mouse carries multiple genetic differences (mutations or polymorphisms) that distinguish it from mice of other strains, although only some of these differences produce phenotypes that are obvious to a biologist. It can be argued that the terms mutant and wild type refer primarily to the interaction of that mouse's genome and its environment rather than the genome alone. Further, this interaction can be very dynamic. The practical implications of these observations may be vital for anyone planning to generate or analyze targeted gene models of epilepsy.

Figure 1 provides a visual schematic that helps to explain the interaction of the genome and the environment as it relates to seizure susceptibility and epilepsy. Six hypothetical mouse strains (A-F) exhibit a low to high risk (left to right) of genetically determined epilepsy within environment 1 (Figure 1A). In this environment, the sum of seizure triggers (theoretical constructs that may occur in the external environment, such as flashing light, loud sound, or in the internal environment, such as hormone levels, blood pressure) present at any one time may range from a level of 0 to about 2.5 (on an arbitrary scale of 0 to 5). This same scale that measures the sum level of seizure triggers can be thought of as measuring an animal's genetic resistance to seizures in that environment. In environment 1, mouse strains D-F (but not strains A-C) exhibit seizures. Figure 1B examines temporal and quantitative aspects of seizures among mouse strains D-F in environment 1. Genetically determined resistance to seizures in each animal (highest in D, lowest in F) is stable over time (dashed lines) because the genome of each animal is stable over the lifespan of that animal, but the level of seizure triggers in environment 1 is highly variable (shaded area). Mouse strain F has such a low intrinsic resistance to seizures (about 0.4) that the sum of seizure triggers is always greater than the threshold for seizures, so that strain F animals would persist in status epilepticus. Strain E has a moderate intrinsic genetic resistance to seizures (~1.3), so that the sum of seizure triggers only occasionally surpasses this threshold; in this example, a mouse from strain E would have a total of five seizures over the period shown (i.e., recurrent seizures, or "epilepsy"). Mice from strain D have a higher intrinsic genetic resistance to seizures (about 2.2). In this example, the seizure triggers in environment 1 surpass the strain D seizure threshold only once over the indicated time period. Figure 1C represents the propensity of an individual mouse (or an entire mouse strain) to appear epileptic in one environment and nonepileptic in another. Here the genetic resistance to seizures across strains remains constant, but environments with different seizure trigger ranges are shown. Mice from strain A (with the highest genetic seizure resistance) do not exhibit seizures in any of the three

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