such as increased neuronal excitability and synchronicity. Emerging insights point to alterations of synaptic functions and intrinsic properties of neurons as common mechanisms underlying hyperexcitability. Progress in the field of molecular genetics has revealed arguments in favour of this hypothesis as mutations of genes encoding ion channels were recently discovered in some forms of human epilepsy.
Epileptic seizures arise from an excessively synchronous and sustained discharge of a group of neurons. The single feature of all epileptic syndromes is a persistent increase of neuronal excitability. Abnormal cellular discharges may be associated with a variety of causative factors such as trauma, oxygen deprivation, tumours, infection and metabolic derangements. However, no specific causative factors are found in many dogs and cats suffering from epilepsy.
Underlying causes and pathophysio-logical mechanisms are (partially) understood for some forms of epilepsy, at least in people, e.g. epilepsies caused by disorders of neuronal migration and monogenic epilepsies. For several other types of epilepsy, current knowledge is only fragmentary. This chapter will review several areas that are understood to contribute to the evolution and maintenance of epilepsy. The genetics of epilepsy are discussed in Chapter 6.
The Electrical Basis of Nerve Cell Function
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.
Synaptic Transmission
Research into seizures has gravitated to mechanisms associated with synaptic transmission, because of its critical role in maintaining the balance between excitation and inhibition. As more research has identified the molecular mechanisms of synaptic transmission, it has become appreciated that defects in almost every step can lead to seizures. Glutamatergic and γ-aminobutyric acid (GABA)-ergic transmission, as the major excitatory and inhibitory transmitters of the nervous system, respectively, have been examined in great detail. It is important to point out, however, that both glutamate and GABA may not have a simple, direct relationship to seizures. One reason is that desensitization of glutamate and GABA receptors can reduce effects, depending on the time-course of exposure. In addition, there are other reasons. GABA-ergic transmission can lead to depolarization rather than hyperpolarization if the gradients responsible for ion flow through GABA receptors are altered. For example, chloride is the major ion that carries current through GABAA receptors, and it usually hyperpolarizes neurons because chloride flows into the cell from the extracellular space. However, the K+Cl− co-transporters (KCCs) that are pivotal to the chloride gradient are not constant. In development, transporter expression changes, and this has led to evidence that one of the transporters, NKCC1, may explain seizure susceptibility early in life (Dzhala et al., 2005). The relationship of glutamate to excitation may not always be simple either. One reason is that glutamatergic synapses innervate both glutamatergic neurons and GABA-ergic neurons in many neuronal systems. Exposure to glutamate could have little net effect as a result, or glutamate may paradoxically increase inhibition of principal cells because the GABA-ergic neurons typically require less depolarization by glutamate to reach threshold. It is surprisingly difficult to predict how glutamatergic or GABA-ergic modulation will influence seizure generation in vivo, given these basic characteristics of glutamatergic and GABA-ergic transmission.
Synchronization
Excessive discharge alone does not necessarily cause a seizure. Synchronization of a network of neurons is involved. Therefore, how synchronization occurs becomes important to consider. There are many ways neurons can synchronize. In 1964, Matsumoto and Ajmone-Marsan found that the electrographic events recorded at the cortical surface during seizures corresponded to paroxysmal depolarization shifts (PDS) of cortical pyramidal cells occurring synchronously (Matsumoto and Marsan, 1964). These studies led to efforts to understand how neurons begin to fire in concert when normally they do not. Glutamatergic interconnections are one example of a mechanism that can lead to synchronization. Indeed, studies of the PDS suggested that the underlying mechanism was a ‘giant’ excitatory postsynaptic potential, although it was debated widely at that time if this was the only cause (Johnston and Brown, 1984). Thus, pyramidal cells of cortex are richly interconnected to one another by glutamatergic synapses. Gap junctions on cortical neurons are another mechanism for synchronization. Gap junctions allow a low-resistance pathway of current flow from one cell to another, so that coupled neurons are
