Читать книгу Canine and Feline Epilepsy - Luisa De Risio - Страница 8

At the most fundamental level, the nervous system is a function of its ionic milieu, the chemical and electrical gradients that create the setting for electrical activity. Therefore, some of the most easily appreciated controls on excitability are the ways the nervous system maintains the ionic environment. An example is the electrical basis of resting membrane potential. Resting potential is set normally so that neurons are not constantly firing but are close enough to threshold so that it is still possible that they can discharge, given that action potential generation is essential to CNS function. The control of resting potential becomes critical to prevent excessive discharge that is typically associated with seizures.

Normally a high concentration of potassium exists inside a neuron and there is a high extracellular sodium concentration, as well as additional ions, leading to a net transmembrane potential of −60 mV (Scharfman, 2007). If the balance is perturbed (e.g. if potassium is elevated in the extracellular space), this can lead to depolarization that promotes abnormal activity in many ways (Somjen, 2002): terminals may depolarize, leading to transmitter release, and neurons may depolarize, leading to action potential discharge. Pumps are present in the plasma membrane to maintain the chemical and electrical gradients, such as the sodium–potassium ATPase, raising the possibility that an abnormality in these pumps could facilitate seizures. Indeed, blockade of the sodium–potassium ATPase can lead to seizure activity in experimental preparations (Vaillend et al., 2002), suggesting a role in epilepsy (Grisar et al., 1992). The sodium–potassium pump is very interesting because it does not develop in the rodent until several days after birth, and this may contribute to the greater risk of seizures in early life (Haglund et al., 1985; Fukuda and Prince, 1992). In addition to pumps, glia also provide important controls on extracellular ion concentration, which has led many to believe that glia are just as important as neurons in the regulation of seizure activity (Duffy and MacVicar, 1999; Fellin and Haydon, 2005). Thus, the control of the ionic environment provides many potential targets for novel anticonvulsants. It is important to bear in mind that seizures, by themselves, can lead to the changes in the transmembrane gradients. For example, seizures are followed by a rise in extracellular potassium, a result of excess discharge. This can lead to a transient elevation in extracellular potassium that can further depolarize neurons. Thus, the transmembrane potential is a control point that, if perturbed, could elicit seizures and begin a ‘vicious’ cycle, presumably controlled by many factors that maintain homeostasis, such as pumps and glia.

The ionic basis of the action potential is another example of a fundamental aspect of neurobiology that can suggest potential mechanisms of seizures. Neurons are designed to discharge because of an elegant orchestration of sodium and potassium channels that rely on chemical and ionic gradients across the cell membrane. Abnormalities in the sodium channel might lead to a decrease in the threshold for an action potential to occur if the method by which sodium channel activation is controlled alters in any way (i.e. sodium channels are activated at more negative resting potentials or sodium channel inactivation is impaired). Indeed, it has been shown that mutations in the subunits of the voltage-dependent sodium channels can lead to epilepsy. A specific syndrome, generalized epilepsy with febrile seizures, is caused by mutations in selected genes responsible for subunits of the voltage-dependent sodium channel (Meisler et al., 2001). The mutation does not block sodium channels, presumably because such a mutation would be lethal, but they modulate sodium channel function. This concept, that modulation, rather than essential function, is responsible for genetic epilepsies, has led to a greater interest in directing the development of new anticonvulsants at targets that are not essential to, but simply influence, CNS function.