Seizures, Epileptogenesis, and Epilepsy

ber of diverse variables. Some of these factors, such as genes that influence seizure susceptibility, are internal. Others, which alter normal brain excitability, such as traumatic brain injury, are external. As described elsewhere in this volume, these variables can AQ? Specific cross-ref to chapter number? have different and distinct effects. For example, genes may influence both the development of the disorder (the epileptogenesis), or the frequency and severity of seizures after epilepsy is established. Furthermore, these same factors may also influence treatment, because they can alter the efficacy of antiepileptic drugs. A broad range of endogenous factors include a subset that can be termed “neuromodulators”. These factors are essential components of the normal central nervous system (CNS) and play an important role in the balance of excitation and inhibition in the normal brain. Here, we review neuromodulatory compounds and principles that best exemplify those that affect seizure susceptibility, epileptogenesis, and epilepsy. In this chapter, neuromodulators are categorized into proteins and small molecules that are (a) primarily expressed in, or released from, neurons; (b) present in the extracellular space as part of the milieu that is commonly referred to as the extracellular matrix (ECM); and (c) primarily associated with astrocytes. This chapter emphasizes neuromodulators that influence excitability in the hippocampus and the adjacent parahippocampal region (including the entorhinal cortex), two brain regions known to be centrally involved in limbic seizure activity. This focus does not imply that neuromodulation is most robust in those areas, but rather reflects the fact that the majority of information in the field of epilepsy research derives from these limbic regions. This includes studies in humans, in which neuromodulation has been mostly examined using surgically resected hippocampal and parahippocampal tissue from patients with intractable temporal lobe epilepsy (TLE). In view of the complexity of the subject matter, often involving multiple receptors as well as intricate modes of regulation of expression and release for any given neuromodulator, only specific examples will be discussed in detail in each category. Furthermore, a major message of this overview is that no single neuromodulator influences excitability in a simple manner, and that cross-talk between modulators is likely to be associated with seizure activity. Tables 1 through 4 provide bulleted lists of the neuromodulator categories that have been associated with pathophysiologically or therapeutically relevant aspects of seizures or epilepsy. Several other relevant categories, such as the neurosteroids, are discussed elsewhere in this volume. The selection included here AQ? Chapter numbers? should be viewed merely as a snapshot of current knowledge. There can be little doubt that additional members of these families will become relevant as well, and that novel, important neuromodulators will be identified in the future.