Neural Basis Of Kindling Research Paper

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The epilepsies are a heterogeneous group of chronic brain disorders characterized by an enhanced susceptibility to spontaneous, recurrent seizures due to the excessive activation of neuronal networks. In recent years a number of widely diverse causes of epilepsy have been identified, including specific gene mutations, developmental defects, and acquired metabolic and structural abnormalities. For example, a mutation in a subunit of the nicotinic acetylcholine receptor is the basis of autosomal dominant nocturnal epilepsy, while other types of epilepsy have been linked to calcium channel defects (Clark and Wilson 1999). Abnormal brain development resulting in dysplasias and other cortical malformations may also lead to epilepsy (Guerrini et al. 1999). At almost any age, injury to the brain due to stroke, trauma, infection, tumors, as well as the adverse effects of alcohol and other neurotoxic substances may be epileptogenic. Despite this diversity, the multiple causes of epilepsy share at least one key feature i.e., they all produce long-lasting changes in neuronal physiology that result in recurrent spontaneous electrical discharges. Identifying the mechanism(s) of epileptogenesis will there- fore lead to a more thorough understanding of brain function and contribute to the development of more effective pharmacologic treatments for epilepsy. While the underlying cellular processes responsible for the epileptic state remain unknown, a great deal of progress has been made in delineating the critical events associated with seizure induction and propagation, as well as epileptogenesis, primarily through the use of animal models. In this regard, the kindling model of epilepsy has played a dominant role.

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1. Definition Of Kindling

In 1967 Goddard demonstrated that daily administration of a subconvulsant electrical stimulus in rats caused a long-lasting change in brain function characterized by the subsequent development of generalized motor seizures. Since this initial report, electrically induced kindling in the mammalian brain has been one of the most widely employed methods to produce recurrent seizures both in i o and in itro. During the initial stages of kindling the inciting electrical stimulus usually produces no overt changes in behavior or electrical activity as measured by an electroencephalogram (EEG) (McNamara et al. 1992). However, with successive stimuli there is associated EEG evidence of hyperexcitability in the form of an after-discharge. Initially, the electrical seizure activity is unaccompanied by behavioral seizures. However, with continued periodic stimulation the duration of the afterdischarge increases along with the development of behavioral seizures. The behavioral stages of kindled seizures in rats can be classified according to the following classes: class 1, facial clonus; class 2, head nodding; class 3, contralateral forelimb clonus; class 4, rearing; class 5, rearing and falling. Once a class 5 seizure is reached, the subject is considered to be fully kindled. In this state, seizures can be elicited by low-level electrical stimulation even after a prolonged stimulus-free interval, indicating that kindling induces permanent alterations in neuronal physiology. Importantly, elicitation of an afterdischarge is required for kindling to occur. In addition to electrical stimulation, after-discharges can be produced by carbachol or other convulsant agents, as well as alcohol, which are used in models of chemical kindling.

2. Kindling Properties

Experimental evidence has demonstrated that different brain regions have varying capacities to develop kindled seizures (Sato et al. 1990). The regions most susceptible to kindling include limbic structures such as the hippocampus, amygdala, and piriform cortex, as well as certain areas of neocortex (Sato et al. 1990, McNamara et al. 1992). Interestingly, there is substantial overlap between epilepsy-prone regions in the rodent brain and those in humans, lending further support to the validity of using kindling models to study epileptogenesis in humans. However, it is important to point out that there are variations between kindling models. In this regard, there are clear differences between the electrophysiological and behavioral features following neocortical stimulation and those following stimulation of limbic structures, such as the hippocampus or amygdala (McNamara et al. 1992). For example, in contrast to amygdala kindling, the afterdischarge produced by stimulation of anterior frontal neocortex may be accompanied by behavioral changes at the outset. The behavioral features, however, are less pronounced than with limbic stimulation. Additionally, seizures evoked by stimulating frontal neocortex are relatively brief when compared to amygdalaor hippocampal-evoked seizures. Although not well understood, these differences may eventually be found to have clinical relevance in terms of modulating the responses to pharmacologic treatment.

The epileptogenic potential of a specific brain region appears to be closely correlated with the rate of kindling i.e., the amount of stimulation required to elicit a class 5 seizure (Sato et al. 1990). Thus, both the amygdala and piriform cortex require the least number of stimulations to reach the kindled state, while hippocampal kindling occurs relatively slowly. Evidence has suggested that increased kindling efficacy, particularly in the amygdala piriform cortex region, may be related to strong connections with motor and other forebrain systems, as well as the presence of highly reactive neurons with pacemaker-like properties (Sato et al. 1990).

3. Kindling Induces Changes In Gene Expression And Cellular Morphology

Investigations employing the compound, 2-deoxyglucose, which labels metabolically active brain regions, have been performed in kindled animals. The results of these studies indicate that the regional pattern of activation following electrical stimulation appears to be stage-dependent i.e., during stages characterized by partial seizures the amygdala and piriform cortex are metabolically labeled, while other areas are subsequently recruited following further stimulation (Ackermann et al. 1986). Activation of brainstem structures such as the substantia nigra has also been reported in kindled animals. Regional increases in metabolic activity in the kindled brain can be correlated with the induction of molecular markers such as the immediate early gene, c-fos (Dragunow and Robertson 1987).

Immediate early genes encode transcription factors that are thought to play critical roles in regulating long-term changes in neuronal function and structure (Sheng and Greenberg 1990). These alterations are likely important in normal brain functions such as learning and memory, as well as pathological conditions such as epilepsy (Sheng and Greenberg 1990). Transient activation of the c-fos gene has been demonstrated in both the hippocampus and piriform cortex of kindled animals (Dragunow and Robertson 1987, Dragunow et al. 1988, Simonato et al. 1991). Moreover, the spatial and temporal patterns of expression of c-fos and other immediate early genes, such as c-jun and NGFI-A, may undergo complex changes following a single afterdischarge (Simonato et al. 1991). These findings suggest that the transcriptional targets of Fos protein and other immediate early gene products may be critical effectors of the long-term modifications in neuronal function that are associated with kindling.

In addition to immediate early genes, kindlinginduced alterations in the expression of growth factors, neuropeptides, and other proteins have been documented (Perlin et al. 1993, Kopp et al. 1999). Increased activity of calcium binding proteins has also been demonstrated in the dentate gyrus of kindled animals, suggesting that intracellular calcium may be an important modulator of epileptogenesis. Increased intracellular calcium associated with oxidative stress may lead to free radical formation and neuronal injury in some kindling paradigms (Rauca et al. 1999).

Kindling-induced effects have also been connected with morphological changes in neurons and astrocytes. Although the contribution of astrocytes and other glial elements needs to be clarified, both astrocyte proliferation and activation have been observed in the hippocampus and amygdala piriform cortex of kindled rats (Sato et al. 1990, Adams et al. 1998). Studies in knockout mice suggest that the astroglial glutamate transporter may play a role in defining the duration of kindled seizures ( Watanabe et al. 1999). Timm staining, a histochemical technique that is widely employed to evaluate synaptic reorganization following neuronal injury in the central nervous system (CNS), has been used in kindling studies (Sutula et al. 1988). An increase in the density of Timm-positive granules in the dentate gyrus of kindled rats supports the notion that mossy fiber collaterals terminate back on their cells of origin and thereby enhance the reactivity of the hippocampus (Sutula et al. 1988). In addition, the compelling results of ultrastructural studies have revealed kindling-induced changes in both the number and type of synaptic terminals, providing a possible anatomical basis for the long-lasting alterations in synaptic function (Geinisman et al. 1992).

4. Excitatory Neurotransmission And Kindling

A discussion of the neural basis of kindling would not be complete without addressing the role of exctitatory and inhibitory synaptic transmission. It is widely held that epileptogenic mechanisms are associated with alterations in the balance between excitatory and inhibitory synaptic functions in the CNS. Excitatory neurotransmission in the mammalian CNS is primarily due to the activation of glutamate receptors (Michaelis 1998). Although the molecular biology of glutamate receptors is beyond the scope of this research paper, it is important to recognize that glutamate receptors are commonly classified on the basis of pharmacological profiles into ionotropic i.e., Nmethyl-D-aspartate (NMDA), α-amino-3-hydroxy-5methyl-4-isoazole propionate (AMPA), and kainic acid (KA) subtypes, as well as ligand-gated metabotropic receptors (Michaelis 1998). Each type of glutamate receptor is formed by an assembly of several subunits (i.e., NMDA receptors have five subunits), all of which have been cloned, sequenced, and functionally characterized. As expected, specific combinations of subunits can assemble into functional glutamate receptors with distinctive physiological and pharmacological properties (Michaelis 1998). Several features distinguish NMDA receptors from the other subtypes of glutamat e receptors. These include a voltage-dependent Mg2+ block of the ion channel that is relieved by depolarization, sensitivity to glycine, and , most importantly, the ability to allow entry of Ca2+, which is itself a key modulator of neuronal excitability (McBain and Mayer 1994).

Among the classes of glutamate receptors, the activation of NMDA receptors appears to play the most prominent role in modulating long-term alterations in synaptic function in the nervous system, a process that is referred to as synaptic plasticity (Mody 1999). NMDA receptor activation has been documented in the kindled state, and changes in specific channel properties have been proposed to form the underlying basis of enhanced NMDA function after kindling (Mody 1999). Among the NMDA receptor related alterations that have been reported with kindling are prolonged channel opening, increased channel phosphorylation, enhanced agonist potency, and alterations in the Mg2+ block (Mody 1999). Evidence has also indicated that such alterations may last for up to one month or longer. In contrast, other studies have demonstrated either no changes in the expression of NMD A subunits, or minimal changes in the binding of L-[3H]glutamate to NMDA receptors after electrical or chemical kindling (Ekonomou and Angelatou 1999, Mody 1999). Additional evidence supporting a prominent role for NMDA receptor activation in the development of kindling is provided by studies employing NMDA antagonists. NMDA receptor antagonists such as aminophosphonovaleric acid (AP5), and channel blockers such as MK-801, are highly effective at inhibiting kindling development (McNamara et al. 1988, McNamara et al. 1992). For reasons that are at present poorly understood, these same antagonists are relatively weak suppressors of seizures in previously kindled animals.

5. Inhibitory Neurotransmission And Kindling

As ligand-gated GABAA receptors are responsible for most of the inhibitory neurotransmission in the mammalian brain, it is reasonable to surmise that repression of GABAergic synaptic inhibition may promote seizure development and kindling. Analogous to glutamate receptors, GABAA receptors are composed of different subunits that assemble into functional channels that regulate Clion conductance, ligand affinity, and sensitivity to modulators (Luddens et al. 1995). Although a decrease in synaptic inhibition may lead to increased neuronal excitation, the role of altered GABAergic synaptic transmission in the development of epilepsy remains controversial. Changes in the expression of GABAA receptor subunit proteins, as well as increased sensitivity of channels to modulation by Zn2+ have been demonstrated (Mody 1999). However, both enhanced GABA binding as well as an increase in the number of GABAA receptors have been reported in the kindled hippocampus (Mody 1999), consistent with increased synaptic inhibition.

Taken together, the results of these and other studies suggest that kindling induces alterations in glutamatergic or GABAergic synaptic functions characterized by effects on either intrinsic channel properties or synapse topology, respectively. Thus, altered synaptic excitation is primarily due to changes in the physiological properties of NMDA receptor channels, while changes in synaptic inhibition are due to alterations in GABAA receptor numbers, subunit composition, and ligand affinity. Whether epilepto-genesis is associated with an imbalance between glutamatergic and GABAergic functions, however, remains to be determined.

6. Relevance Of Kindling To Human Epilepsy

Because of the strong correlation with long-term alterations in brain function the kindling model is highly relevant to the study of chronic epilepsy in humans. In this regard, it is important to recognize that the permanent changes produced by periodic subconvulsant stimuli distinguish kindling from other seizure models i.e., electroshock or the administration of compounds such as pentylenetetrazol, in which single seizures are produced in an otherwise normal brain. This has important ramifications for pharmacotherapy, as agents that may be effective anticonvulsants in single seizure models may not prevent kindling-induced seizures. One example is the NMDA receptor channel blocker, MK-801, which inhibits electroshock-induced but not kindled seizures (McNamara et al. 1988). In addition, a distinction must also be made between drugs that are anticonvulsant and those that are antiepileptogenic. Accordingly, compounds such as MK-801 may be more effective at inhibiting the development of kindling (i.e., antiepileptogenic) rather than kindled seizures (anticonvulsant), while other drugs such as carbamazepine may block kindled seizures but not kindling development (Sato et al. 1990). Further, drugs that have both antiepileptogenic and anticonvulsant properties (i.e., valproic acid) may provide greater therapeutic efficacy against epilepsy. It is therefore important to include the kindling model in drugscreening programs aimed at identifying antiepileptogenic compounds for use in humans.

Additional similarities to human epilepsies provide further rationale supporting the use of the kindling model to study human epileptogenesis. Many of the behavioral and electroencephalographic features of kindled seizures in rodents bear a striking resemblance to those of temporal lobe epilepsy in humans. Surprisingly, attempts to produce complete kindling (i.e., class 5 seizures) in nonhuman primates have met with limited success. Although class 4 and class 5 seizures can be elicited in baboons, experimental evidence has suggested that there may be strain-dependent differences in the susceptibility of nonhuman primates to kindling (Sato et al. 1990). Nonetheless, the ability to induce kindling in nonhuman primates supports the idea that a kindling-like mechanism plays an important role in the development of epilepsy in humans. In addition, several groups have reported the development of recurrent seizures in patients who have received repeated periodic electrical stimulation to the brain for the treatment of either schizophrenia or chronic pain (Sato et al. 1990). These observations lend strong support to the idea that kindling does occur in humans.

If the kindling pathway is a critical component in human epileptogenesis, then the identification of pathophysiological conditions that may promote kindling becomes increasingly important. There is accumulating evidence suggesting that a focal brain injury may lead to increased neuronal excitability and repetitive discharges that, under certain circumstances, may kindle surrounding structures. In addition, it has been recently proposed that hippocampal damage due to febrile seizures in early childhood may lead to focal neuronal hyperexcitability resulting in the development of temporal lobe epilepsy (Chen et al. 1999). This idea is supported by investigations using glutamate analogues such as kainic acid (KA). Selective neuronal degeneration following KA treatment results in sprouting of hippocampal granule cell axons and formation of recurrent excitatory synapses that may result in abnormal repetitive discharges and a kindling-like process (Routbort et al. 1999).

7. Summary

Kindling is a phenomenon that is characterized by a progressive and long-lasting increase in seizure susceptibility, or epileptogenesis, resulting from the administration of periodic subconvulsant electrical or chemical stimuli. The electrophysiological and behavioral features of kindling have been well defined and may vary with brain region. Limbic and specific neocortical regions have the greatest potential for kindling. Kindling-induced brain activation is associated with altered gene and protein expression in neurons and glia, as well as morphological changes that contribute to long-lasting modifications in neuronal structure and function. Additionally, changes in both excitatory glutamatergic and inhibitory GABAergic synaptic neurotransmission have been demonstrated in the kindled brain. Similarities between the kindling model and human epilepsies provide further justification for using kindling to study epileptogenesis in humans. Recent evidence suggests that a kindling-like process may lead to the development of epilepsy following a focal injury to the brain. A more thorough delineation of the cellular and molecular events underlying kindling will therefore provide a greater understanding of epileptogenesis in the human brain, and could lead to the development of more effective antiepileptic treatments.


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