Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintainance of epilepsy

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Abstract

Epilepsy is one of the most common neurological disorders. Although epilepsy can be idiopathic, it is estimated that up to 50% of all epilepsy cases are initiated by neurological insults and are called acquired epilepsy (AE). AE develops in 3 phases: (1) the injury (central nervous system [CNS] insult), (2) epileptogenesis (latency), and (3) the chronic epileptic (spontaneous recurrent seizure) phases. Status epilepticus (SE), stroke, and traumatic brain injury (TBI) are 3 major examples of common brain injuries that can lead to the development of AE. It is especially important to understand the molecular mechanisms that cause AE because it may lead to innovative strategies to prevent or cure this common condition. Recent studies have offered new insights into the cause of AE and indicate that injury-induced alterations in intracellular calcium concentration levels [Ca2+]i and calcium homeostatic mechanisms play a role in the development and maintenance of AE. The injuries that cause AE are different, but they share a common molecular mechanism for producing brain damage—an increase in extracellular glutamate concentration that causes increased intracellular neuronal calcium, leading to neuronal injury and/or death. Neurons that survive the injury induced by glutamate and are exposed to increased [Ca2+]i are the cellular substrates to develop epilepsy because dead cells do not seize. The neurons that survive injury sustain permanent long-term plasticity changes in [Ca2+]i and calcium homeostatic mechanisms that are permanent and are a prominent feature of the epileptic phenotype. In the last several years, evidence has accumulated indicating that the prolonged alteration in neuronal calcium dynamics plays an important role in the induction and maintenance of the prolonged neuroplasticity changes underlying the epileptic phenotype. Understanding the role of calcium as a second messenger in the induction and maintenance of epilepsy may provide novel insights into therapeutic advances that will prevent and even cure AE.

Introduction

Epilepsy is a neurological disorder characterized by recurrent, unprovoked seizures. A seizure is the symptomatic, behavioral manifestation of abnormal, disordered, spontaneous, and synchronized, high-frequency firing of populations of neurons in the central nervous system (CNS; Lothman et al., 1991, McNamara, 1994, McNamara, 1999). The overt behavioral signs and symptoms associated with a seizure are, in large part, attributed to the normal function of the involved neurons; therefore, seizure expression can be diverse (Hauser & Hesdorffer, 1990). Epilepsy can also vary in age of onset, cause, seizure type, and pattern of the electroencephalogram (DeLorenzo, 1989, DeLorenzo, 1991). This diversity of expression has led to the standard classification of epilepsy and the numerous different epilepsy syndromes (Frazen, 2000). Although epilepsy can manifest itself in a number of different ways, each type of epilepsy shares the common feature of persistently increased neuronal excitability that manifests sporadically as seizure generation (Lothman et al., 1991, McNamara, 1994, McNamara, 1999).

Epilepsy is a common condition affecting ∼1–2% of the population worldwide (Hauser & Hesdorffer, 1990, McNamara, 1999). Studies from the United States, Europe, China, and Africa report prevalence rates between 5 and 8 per 1000 (Dowzendo & Zielinski, 1971, Hauser & Kurland, 1975, Li et al., 1985, Haerer et al., 1986, Osuntokun et al., 1987, Hauser & Hesdorffer, 1990). The incidence of epilepsy is slighter higher in men than in women (Annegers, 1993) and appears to be higher in African-Americans than in Caucasians (Haerer et al., 1986). With exclusion of all other known factors, age alone constitutes a risk for epilepsy with a magnitude of 1.3 for every decade of life over the age of 30 (Ng et al., 1993). Interestingly, this age dependence of the incidence of epilepsy has shifted over recent years. Whereas the majority of epilepsies were once manifested in childhood and adolescence, today, the incidence is higher in persons over the age of 65 than during the first 2 decades of life (Kramer, 2001). In fact, epilepsy is the third most frequent neurological disorder encountered in the elderly after cerebrovascular disease and dementia (Kramer, 2001). In addition to epilepsy, population-based epidemiological studies demonstrate that status epilepticus (SE), a severe form of seizures, has a much greater incidence than previously reported and like epilepsy, also manifests the highest incidence in childhood and in the elderly, and is often present as the first seizure type in the development of epilepsy (DeLorenzo et al., 1995, DeLorenzo et al., 1996, DeLorenzo, 1997)

Epilepsy impacts society on multiple levels. From an economic standpoint, the total annual cost of epilepsy is estimated at nearly US$4 billion in direct medical expenses combined with indirect expenses such as lost wages, cost of home care, and premature death (Murray et al., 1996). The cost of SE is even higher (Penberthy et al., in press). Although advances have been made in the development of new anticonvulsant drugs and the surgical treatment of epilepsy, ∼50% of epilepsy cases remain refractory to medical interventions and epilepsy greatly burdens the quality of life of 1–2 million Americans (Hauser & Hesdorffer, 1990). In daily life, both refractory epileptic patients, as well as epileptic patients dealing with constant management issues of treatment, can suffer from limitations in mental and physical functions, difficulties in employment status of both the individual and the family caregivers and altered interpersonal relationships at work, home, and school (Cramer et al., 1999, Buelow, 2001). Thus, the stigma associated with epilepsy, as well as functional disabilities of the disease, can greatly diminish the quality of life of persons with epilepsy (Beghi et al., 2004, Benavente-Aguilar et al., 2004, McEwan et al., 2004).

Although a significant number of epilepsy cases are idiopathic, it is estimated that up to 50% of epilepsy cases are associated with a previous neurological insult and are called acquired epilepsy (AE; DeLorenzo, 1989, DeLorenzo, 1991, Hauser & Hesdorffer, 1990). The other 50% of epilepsy cases occur in the absence of other brain abnormalities (Frazen, 2000). These epilepsies are called idiopathic, in that there is no known cause for the manifestation of epilepsy. Ongoing research in the field of medical genetics has led to the recent elucidation of an underlying cause for some of these idiopathic cases with the identification of cell migration abnormalities (Copp & Harding, 1999, Rakic, 2000, Lee et al., 2001, Haas et al., 2002, Sato et al., 2003) and numerous gene mutations in humans (Bertrand et al., 1998, Biervert et al., 1998, Wallace et al., 1998) and mouse models of epilepsy (Puranam & McNamara, 1999) that may underlie some of these idiopathic epilepsies. However, in the majority of idiopathic cases, the underlying cause of the epileptic phenotype is still not known.

In the remaining half of epilepsy cases, a known cause or injury produces a permanent plasticity change in a previously normal brain leading to the development of AE (Hauser & Hesdorffer, 1990, Lothman et al., 1991, McNamara, 1999). This transformation of healthy CNS tissue with a functional balance between excitation and inhibition to brain tissue having a hyperexcitable neuronal population of neurons is called epileptogenesis (Lothman et al., 1991, McNamara, 1999, DeLorenzo, 2004). Although genetic determinants may increase the risk that an insult to, or abnormality of, the CNS would trigger epileptogenesis (McNamara, 1999), this review will focus on the cellular and molecular events initiated by injury that culminate in AE. CNS injury is the major cause of AE (Hauser & Hesdorffer, 1990). A thorough understanding of the signaling cascades associated with the development of epileptogenesis and maintenance of the chronic epileptic state are required for understanding the development of AE and for developing novel interventional protocols to prevent or even cure AE (Stables et al., 2002). This review will focus on the basic mechanisms underlying injury-induced AE and the evidence that Ca2+ is a major second messenger that may play an important role in the development and maintenance of AE.

SE, stroke, and traumatic brain injury (TBI) are the 3 major examples of common brain injuries that can lead to the development of AE. These injuries, despite differences in the inciting event, share a common molecular mechanism for producing brain damage: an increase in extracellular glutamate concentration that has been associated with neuronal death and brain damage (Choi, 1988, Michaels & Rothman, 1990, Tymianski, 1996). The mechanisms of glutamate excitotoxicity have been well characterized and shown to associate excessive stimulation of glutamate receptors and a concomitant overwhelming increase in free intracellular calcium concentration levels ([Ca2+]i) with over stimulation of Ca2+ signaling pathways leading to neuronal death (Choi, 1988).

Calcium is a major signaling molecule in neurons, and as such, neuronal free [Ca2+]i is highly regulated. Brief, controlled elevations in Ca2+ occur during physiological processes such as neurotransmitter release and the plasticity changes of long-term potentiation in learning and memory (Malenka & Nicoll, 1999, Gnegy, 2000, West et al., 2001, Tzounopoulos & Stackman, 2003). In contrast, overwhelming, irreversible elevations in [Ca2+]i, as observed in glutamate excitotoxicity, have been implicated in mechanisms of delayed neuronal death secondary to SE, stroke, and TBI. The Ca2+ hypothesis of epileptogenesis postulates that the pathophysiological effects of Ca2+ on neuronal function may lie on a continuum with one extreme characterized by brief, controlled Ca2+ loads of normal function, another extreme characterized by irreversible Ca2+ loads and neuronal death, and a middle ground that is characterized by sublethal, prolonged, but reversible, elevations in [Ca2+]i that trigger pathological plasticity changes, leading to the development of epilepsy and the persistent elevations in [Ca2+]i that are associated with the epileptic phenotype play a role in maintaining chronic epilepsy. Thus, after a CNS injury, neurons via several mechanisms undergo elevations in [Ca2+]i. If the injury is sufficiently severe, the Ca2+ overload becomes irreversible leading to neuronal death. However, a less severe, epileptogenic CNS injury can lead to prolonged elevations in [Ca2+]i that are eventually buffered by neurons. The Ca2+ hypothesis of epileptogenesis proposes that these surviving neurons in the face of extended Ca2+ exposure undergo plasticity changes leading to epilepsy.

After a CNS insult, in the context of a relatively complicated set of variables including injury severity, anatomic location, physiological redundancy, and genetics, the complete spectrum of Ca2+ changes can occur at one time in different areas of the injured brain. Inherent to the Ca2+ hypothesis of epileptogenesis is the relatively, simple conception that dead neurons do not seize. Thus, neurons that survive a CNS injury are the potential substrate for the development of epilepsy. The purpose of this article is to review and summarize the evidence that long-term alterations in neuronal Ca2+ function in neurons that survive a brain insult underlie both the development and maintenance of the epileptic condition.

Furthermore, targeting alterations in Ca2+ homeostatic mechanisms induced in the development of AE may offer novel strategies for the development on new anticonvulsant, antiepileptogenic, and possibly agents that may cure AE (DeLorenzo, in press). Thus, understanding the role of Ca2+ in the development and maintenance of AE may offer important clinically relevant strategies to prevent or possibly cure this common neurological condition.

Section snippets

Central nervous system injuries that produce acquired epilepsy

Epileptogenesis can be initiated by a number of types of brain lesions (Herman, 2002) and these numerous etiologies vary with age (Anderson et al., 1999). Illness in the form of tumors, infections, and degenerative diseases all increase the incidence of AE (Annegers, 1993). Developmental deficits, such as cerebral palsy, are the major risk factor for epileptogenesis in children and account for 18% of all AE cases (Hauser et al., 1991). The 3 major injuries to the brain produce the majority of

Pathophysiology of epileptogenic central nervous system insults

As characterized by epidemiological studies, many types of injuries to the CNS can result in epileptogenesis (Herman, 2002). The most common causes of AE (SE, stroke, and TBI) are caused by different initial injuries, but they share a common mechanism for producing neuronal injury: the production of a pathological increase in the concentration of extracellular glutamate and an associated increase in [Ca2+]i. These injuries can result in a spectrum of brain damage: (1) in some circumstances

Glutamate excitotoxicity: a common mechanism underlying epileptogenic central nervous system insults that cause elevated Ca2+

Among a host of candidate mechanisms, one common thread underlying each of the epileptogenic CNS insults described above is an elevation in the extracellular concentration of glutamate and excessive activation of various subtypes of glutamate receptors. Olney and de Gubareff (1978) coined the term “excitotoxicity” to broadly describe the ability of excitatory amino acid neurotransmitters to cause neuronal death, presumably by prolonged excitation and energy depletion. Since the early

Calcium as a common denominator in the injury phase of acquired epilepsy

Since Ca2+ entry through the NMDA receptor channel complex has been shown to be central to producing the initial insult associated with the injury phase of SE, stroke, and TBI, it is important to understand the role of Ca2+ in excitotoxic neuronal injury and death and how the neuron controls Ca2+ homeostasis. The following material reviews how Ca2+ is regulated in neurons and provides an insight into the potential alterations that occur in controlling [Ca2+]i levels during and after the injury

Dead cells do not seize: Surviving neurons are the substrate for epileptogenesis

Another concept original to stroke that has been extended to SE and TBI is the concept of the penumbra. The ischemic penumbra represents a region of injured brain tissue that is not necessarily destined to die. As described earlier, the ischemic penumbra undergoes a less severe, transient ischemia during stroke secondary to collateral cerebral vasculature (Vaughan & Bullock, 1999), which leads to less severe increases in extracellular glutamate in the penumbra. Thus, the damage in the penumbra

Experimental models of injury-induced spontaneous recurrent seizures

A number of research models have been utilized to demonstrate chronic neuronal hyperexcitability after stroke, SE, and TBI in both whole animal and in vitro systems. While some systems have demonstrated overt seizure expression, others have only demonstrated electrographic seizures. Still, others have only demonstrated a chronic shift towards enhanced excitability. These models are important in providing the substrate to evaluate the basic mechanisms underlying the role of Ca2+ in AE.

A calcium continuum from epileptogenesis to excitotoxicity

A major theory in developing the role of Ca2+ in the development of AE is that there is a continuum of severity in the effects of Ca2+ on neuronal tissue. Olney (1969) initially developed this concept in the discovery of excitotoxicity. This concept indicates that small changes in Ca2+ levels produced by glutamate receptor stimulation results in physiological activities related to synaptic transmission and normal physiological activity. However, excessive activation of the glutamate receptors

Calcium and the induction of epileptogenesis

Ca2+ homeostasis is essential to normal neuronal function (DeCoster et al., 1992, Tymianski & Tator, 1996, Berridge, 1998), and irreversible Ca2+ overload leads to neuronal death after CNS injuries such as stroke (Choi & Rothman, 1990, Tymianski & Tator, 1996, Kristian & Siesjo, 1998, Lipton, 1999). The Ca2+ hypothesis of epileptogenesis suggests that a more moderate neuronal insult producing prolonged but reversible elevations in [Ca2+]i through the activated NMDA receptor contributes to the

Calcium and the maintenance of acquired epilepsy

The Ca2+ hypothesis of epileptogenesis proposes that persistent alterations in Ca2+ homeostasis also underlie the maintenance of the epileptic condition. Whereas Ca2+ overload and irreversible loss of Ca2+ homeostasis have been implicated in excitotoxic neuronal death (Limbrick et al., 1995), long-lasting changes in normal Ca2+ handling, below threshold for excitotoxic cascade activation, may sustain the pathophysiological changes associated with the expression of spontaneous recurrent

Effects of elevated [Ca2+]i and altered calcium homeostatic mechanisms in the chronic phase of acquired epilepsy on calcium-dependent signaling cascades

It has now been established in multiple models of AE that the epileptic phenotype is associated with elevated [Ca2+]i and altered Ca2+ homeostatic mechanisms in neurons in the hippocampus and possibly in other areas of the brain. Since Ca2+ is such a major second messenger system affecting many aspects of neuronal function, it is reasonable to assume that this underlying change in [Ca2+]i plays a major role in altering neuronal activity. Although it is still not possible to clearly define which

Implications for the development of novel anticonvulsant drugs, antiepileptogenic agents and potential therapies to possibly reverse acquired epilepsy

Understanding the role of Ca2+ as a second messenger in AE, may provide important insights into the molecular basis of the development of epileptogenesis. Although changes in Ca2+ second messenger effects in the development of AE are unlikely to explain all of the complex changes associated with the development of AE, the demonstration of alterations in Ca2+ systems in all 3 phases of the development of AE offer an important starting point for further exploration of the role of Ca2+ second

Acknowledgments

This research was supported by NIH grants RO1-NS and P50-NS. We would also like to thank our research colleagues, Dr. Robert Blair, Dr. Sompong Sombati, Dr. S.B. Churn, Dr. Douglas Coulter, Dr. David Limbrick, Dr. Michael Miles, and Dr. Steven Shapiro for their encouragement and suggestions over the years in developing this work. The encouragement and support of Dr. Michael Rogawski were greatly appreciated.

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    Current Address: Department of Neurosurgery, Vanderbilt University, School of Medicine.

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