Molecular And Cellular Aspects Of Epilepsy Biology Essay

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Epilepsy is a most prevalent neurological disease found on earth that is characterized by frequent onset of seizures. This disease was considered sacred in the past because of its unusual signs and symptoms shown by a patient. Epilepsy is basically an electrical event of brain with sudden onset and is characterized by hyper excitability and hyper synchronization of large group of neurons. Epilepsy can be originated at any stage of life from childhood to old, to any human being. This syndrome has lot of causes and is also considered as idiopathic and thought to have Mandelian inheritance. It occurs because of changes in patterns of neuronal excitability due to loss of balance between excitatory and inhibitory neurotransmitters, malformation in ion channel functions and also related to cerebral injury. In this review, cellular and molecular aspects of epilepsy are covered that include hyperexcitabiltiy of neurons, role of different ion channel functions in propagation of disease, imbalance of excitatory and inhibitory neurotransmitters generating disease and few genetic causes of disease.


The earliest medical writings on epilepsy are found on Egyption papyri and Babylonian cuniform tablets in which they thought the disease was caused by ghosts and demons that controlled some individual (Kinnier and Reynolds, 1990). The first book on epilepsy was wrote by Greek physician Hippocrates, 'On The Sacred Disease' and he believed the disease as a physical disorder of brain and not curse from gods but called it sacred (Shawn et al., 1999). Epilepsy is a disorder of brain characterized by an enduring tendency to produce epileptic seizures and by the neurobiologic, psychological, cognitive and social consequences of this condition. The definition of epilepsy requires the episode of at least one epileptic seizure. An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in brain. A seizure consists of synchronized firing of large number of neurons. There are two main types of seizures. In primary generalized seizure, there is involvement of thalamacortical circuitry thus resulting in synchronized firing of neurons all in brain with unconsciousness and often violent shaking of body parts. While in case of focal seizures, the synchronized activity is usually restricted to only one part of cortex (Fisher et al., 2005). Epileptic syndromes are defined according to type of seizures, age of onset, neuroimaging, electroencephlography and other features (Crompton and Berkovic, 2009). The initiation and propagation of epileptic seizure is thought to occur due to imbalance between depolarizing and hyperpolarizing influences in highly interconnected neuronal population (Richichi et al., 2008).

Epileptic seizures and syndromes can be of focal or generalized origin while there causes may be symptomatic (including tumors, stroke, cortical malformations etc) or idiopathic (ILAE, 1989). Idiopathic epilepsies are mainly thought of as having genetic origin and are assumed to represent 47% of all epilepsies (Freitag et al., 2001). The role of neuroimaging is important in investigating functional consequences of gene defects within epilepsy. Neuroimaging also help to specify phenotypic expression with better characterization of phenotype-genotype interaction (Siniatchkin and koep, 2009). A transient and involuntary change in behavior or neurologic status because of abnormal activity of population of neurons of CNS is referred to as a seizure. A condition with recurrent seizures of neuronal origin refers to as epilepsy. Normal function of CNS depends on the initiation and transmission of excitatory impulse from one region to another. Most of the neurons in brain are excitatory and utilize glutamate as excitatory neurotransmitter (March, 1998). A minor change in normal neuronal circuit excitability because of increased recurrent excitation, increased inherent excitability or deficient recurrent inhibition or all of them can be the cause of epileptogenesis. Thus, any disturbance in normal cerebrocortical function can induce seizure (Meldrum, 1994). At resting state, the inside of cell is more negative then outside and the neuron is said to be polarized. It is a resting membrane potential with -70mV and is maintained by complex phenomenon, as the plasma membrane is selectively permeable to retain ions, retain more organic anions intracellular and by an energy dependent sodium-potassium pump. This pump pushes sodium out of the cell and pumps potassium into the cell. The plasma membrane is highly permeable to potassium and less permeable to sodium and other cations, at rest. A state of depolarization occurs when there is change in permeability of cell to sodium or calcium resulting in influx of positive charge. A wave of depolarization is initiated in the form of excitatory post-synaptic potential or action potential in other parts of cell. The cell becomes hyper polarized if the plasma membrane becomes selectively permeable to chloride anions because of influx of negative charge and inhibitory post-synaptic potential is generated. Most ion channels are voltage gated or ligand gated. Pre-synaptic release of neurotransmitters cause the activation of post-synaptic ligand gate ion channels while voltage gated ion channels are activated by membrane polarizations. The cellular alterations involved in epileptogenesis include neuronal cell death, neurogenesis, mossy fiber sprouting and gliosis etc.

The prevalence of epilepsy is worldwide affecting fifty million people and is referred to as chronic neurological disorder (Duncan et al., 2006). Control of epileptic seizures by anticonvulsant drugs is effective in 70% of the patients (Sillanpaa and Schimidt, 2006). This review focuses on the current knowledge of the epileptic mechanisms involving cellular, molecular and genetic aspects.

Neuronal Excitability in Epilepsy

Epileptic seizures arise because of enormous discharge produced by a population of hyper excitable neurons. In most of the epileptic seizures, the discharges are in cortical and hyper cortical regions of brain. In this regard the clinical expression of seizure is dependent on site of origin, time course and discharge propagation. Epileptic seizures are the result of neuronal excitability which may originate from individual neurons, neuronal environments or population of neurons. When membrane or metabolic properties of neurons are altered or when extracellular concentrations of ions or neurotransmitters is suboptimal, these collective anatomic or physiologic neural alterations convert neurons to hyper excitable populations (Traub et al., 1996). The development of burst activity depends on the net inward current and not on its absolute magnitude. In epileptic neurons, there is increase calcium conductance as latent calcium channels are used that increased efficacy of calcium channel or chronic increase of number of calcium channels. The potassium equilibrium across the neuronal membrane is reduced when extracellular potassium concentrations are increased resulting in reduced outward potassium current. There is inward net current that causes the depolarization of a neuron to an extent that trigger calcium current, resulting in burst of spikes (Ditcher, 1997). There are functional as well as structural changes occur in epileptic foci. Functional include metabolic alterations, concentration of cations and anions and changes in neurotransmitter level whereas structural changes involve neurons and glia. Neuronal depolarization leading to spike discharge occurs because of excessive extracellular potassium. There is decrease in extracellular calcium preceding those of potassium and calcium level goes to normal at a faster rate than potassium in a particular seizure (Engelborghs et al., 2000). The mechanism is shown in figure 1. The role of glia is to clear extracellular neurotransmitters and buffering potassium in a way to correct the increased extracellular potassium concentration during a seizure. There is glial proliferation in epileptic foci and gliosis found to affect glial buffering capacity contributing to generation of seizure (Grisar et al., 1999). Decrease in inhibitory influence and increase in excitatory affects are produced due to both anatomical, physiological alterations of neurons. Mossy fiber sprouting is an example of neuronal alteration causing increase excitability and hence epilepsy (Cavazos et al., 1991).

Figure 1. Ions involvement in membrane excitability. Three mechanisms by which ions cross the cell membrane, through ion pumps (yellow), ligand gated channels (blue) and voltage sensitive channels (orange).

Ions Channels and Epilepsy

There is a passive diffusion of ions through the biological membrane from the pores of ion channels. These ion channels are specific for different ions including sodium, potassium, calcium, chloride and some unspecified cation channels. Movement of ions across is dependent upon electrochemical gradient which is formed by movement of active pumps, co-transporters and ion channels. Gating is a process by which ion channels open and close, allowing many type of regulation as ligand gated and voltage gated channels. Ions cannot move through the neuronal cytoplasmic membrane because of its impermeable nature but can be actively transported across the membrane by ionic pumps and on the basis of their electrochemical gradient move through voltage gated and ligand gated channels. Ionic pumps are responsible for creating and maintaining resting membrane potential while changes in excitation state are because of gated channels. In nervous system, ion channels generate, repress and propagate action potentials. Neuronal depolarization is observed on opening of sodium channels while hyper polarization is observed on opening of potassium channels. Calcium ions have depolarizing effects while chloride ions have both hyper polarizing and depolarizing effects. This can be correlated in a way that if there is loss of function mutation in neuronal potassium channel lead to hyper excitability of neurons thus causing epilepsy (Hubner and Jentsch, 2002).

There is an equilibrium potential maintained between intracellular and extracellular compartments. There are ATP dependent sodium and potassium pumps that move sodium from inside to outside while potassium from outside to inside. Thus inside is more negative resulting in a resting membrane potential of -70mV. Ions move selectively through voltage gated and ligand gated channels and generates transient changes in membrane potential (Avanzini and Franceschetti, 2003). Ion channels are basically hetero-oligomeric membrane proteins composed of two to six subunits comprising of transmembrane segments assembled with different domains (Green and Miller, 1995). A model is shown in figure 2. In an epileptic seizure there is an aggregate of neurons that produce protracted bursts of action potentials called paraoxysmal depolarization shifts. There is a synchronization pattern among these neuronal aggregates (Matsumoto and Marsan, 1964). In case of focal epilepsies, these paraoxysmal depolarization shifts are the indicators of provoking epileptic condition (Prince, 1985).

Figure 2. Structure of voltage dependent potassium channel and cylinder represents helical membrane spanning six domains.

Rising phase of the action potential is caused by the fast inactivating and transient current flowing through the sodium channels. Agents that block these fast inactivating channels and continue this sodium current can in turn cause the neurons to burst firing rather than regular spiking. Molecular changes in the structure of sodium channels cause the same described mechanism leading to epilepsy (Wallace et al., 1998). There are different types of potassium currents observed; out of all these is M current which is relatively important in controlling neuronal excitability. It is called M because when muscarinic acetylcholine receptors are activated these are inhibited. The M current is dependent on slow activating conductance active between -60mV and -20mV. Thus M current is responsible for controlling sub-threshold membrane excitability and synaptic input. Burst activity is generated when muscarine binds to its receptor. There are mutations found in the M current, as two potassium channels contribute to it and mutations in either of the genes lead to bursting and convulsions (Wang et al., 1998). The role of calcium channel in the pathogenesis of naturally occurring epilepsy is rather difficult to find because of different calcium currents and their different roles, however experiments done on rat models show absence epilepsy found to be related with calcium channel disturbances (Burgess and Noebels, 1999).

There are two main types of EAA receptors, as AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) and NMDA (N-methyl-D-aspartate). Sodium ions have the access through the ionophores of both the receptors while calcium ion got their permeability only through NMDA. Magnesium ions are capable of blocking the NMDA receptors, which have long lasting depolarizing events, in a voltage dependent manner. Depolarization of this channel is required for the inward movement of sodium and calcium currents, which is achieved when magnesium block is removed. The neurotransmitters for EAA receptors are glutamate and aspartate (Maden, 2002). The inward current of sodium and potassium through NMDA are powerful enough to maintain membrane depolarization and can increase and prolong EAA mediated excitatory postsynaptic potential. The agonists of EAA receptors such a hybotenic acid and kainic acid have been found to induce epilepsy in animal models indicating the role of EAA receptors in epileptogenesis (Najm et al., 2000).

Epilepsy is the result to malformation in the balance between excitatory and inhibitory neuronal networks. The communication between neurons and their excitability is based on axonal conduction mediated by action potentials and on signal transduction mediated by synaptic transmission. These two important processes are mainly related with ion channels. Influx of sodium and efflux of potassium ions initiate electrical impulse in neurons. This electrical signal is converted to chemical one by the influx of calcium ion in axon terminal and in this way neurotransmitters are released in the synapse. This neurotransmitter binds to its receptor and subsequent ion flux is responsible for the initiation of electrical impulse in the downstream neuron. If there is any change in these processes of brain, the epileptic seizures are induced (Roll and Szepetowski, 2002).

Ion channels are the transmembrane proteins containing selective pores for different types. ligand binding, voltage, cell volume, intracellular ions or neucleotides are responsible for the activation of ion channels,. Ligand gated channels are activated by different neurotransmitters such as glutamate, glycine, acetylcholine or GABA. When ligand binds then channel opens. These ligand gated channels are proteins with several subunits. These subunits have same kind of structure with 2-4 transmembrane domains. Their M2 domain forms active pore that is permeable to anion or cation. The gene CHRN4 encodes neuronal nicotinic acetylcholine receptor α4 subunit, the mutation in it lead to alteration in M2 domain, thus alteration in active pores (Steinlein et al., 1995). Mutations are also observed in CHRNB2 gene that encodes β2 subunit of acetylcholine receptors (Phillips, 2001). Because of these mutations, the channel activity is decreased and the calcium flux through the receptor is reduced. This results in synaptic disinhibition and thus induction of epileptic seizures (Steinlein et al., 1995). The other ligand gated ion channels are GABAA receptors that cause hyper polarization of neurons by increasing inward chloride conductance. Two mutations are observed. One in benzodiazepine binding domain of protein whiles other missense mutation in M2 and M3 transmembrane domain leading to hyper excitability (Roll et al., 2002).

Table 1. Implicated ion channels in epilepsy.




Voltage Gated

Sodium channel


Type1 α1 subunit


Type1 β1 subunit


Type2 α1 subunit

Calcium channel


P/Q-Type α1 subunit



T- Type1 α1 subunit

Potassium channel


Kv 1.1





BK channel

Chloride channel



Ligand Gated

Acetylcholine receptor


β2 subunit


α1 subunit

GABA receptor


γ2 subunit


α1 subunit


β subunit

Voltage gated channels at resting membrane potential are in closed states. The gates of these channels open at depolarization of cell membrane. Voltage gated channels share a common domain structure and are composed of several subunits. Α domain is the main one that plays gating and permeation roles and each domain are composed of six transmembrane segments, S1-S6 loop. β1 chain of voltage gated sodium channel is encoded by SCN1B gene and mutations are found in this leading to epilepsy (Wallace et al, 1998). Mutation in SCN1A is also observed (Claes et al., 2001). The KCNQ gene subfamily is composed of five delayed rectifier potassium channels and this KCNQ1-5 contribute to re-polarization of action potentials. Products of KCNQ2 and KCNQ3 are associated with the production of M currents. A moderate loss of M current leads to neuronal hyperexcitability as found in KCNQ2 and KCNQ3 mutations (Schroider et al., 1998). The prolonged sodium currents are observed when there is loss of function of KCNA1 potassium channel. This KCNA1 is a voltage gated potassium channel that takes part in recovery phase of action potential. Mutations in KCNA1 are found in different cases (Smart et al., 1998).

Neurotransmitters and Epilepsy

The endogenous chemicals that are responsible for transmitting signals from a neuron to a target cell are called neurotransmitters. There are many neurotransmitters some of which are excitatory e.g. glutamate and some are inhibitory e.g. GABA (γ amino butyric acid). These have very important role in epilepsy. When there is reduction of GABA-ergic inhibition then outcome is epilepsy while opposite to that as enhancement of GABA-ergic inhibition results in anti-epileptic effects. Studies on epileptic foci in animal models suggest that there is reduced level of GABA and glutamic acid decarboxylase activity in epilepsy (DeDeyn et al., 1990). A key role in epileptic phenomenon is being played by glutamatergic synapsis. A proconvulsant affect is associated with the activation of metabotropic and ionotropic postsynaptic glutamate receptors. In many animal models of epilepsy, antagonists of NMDA receptors are prove to be convulsants. In epilepsy, an increase sensitivity to the action of glutamate on NMDA receptor results in enhanced entry of calcium into neurons during synaptic activity (Lovvel and Pumain, 1992). Alteration in metabotropic glutamate receptor function has an important role in epileptogenesis (Chapman, 1998). In epilepsy, plasma glutamate levels are found to be increased. An increased amount of glutamate in plasma, thus neuronal membranes get more glutamate leading to neuronal excitability (Van Gelder et al., 1980). It is found out that decrease dopamine facilitates onset of seizures by lowering threshold triggering such seizures. Thus decreased levels of dopamine have been found in epileptic foci of patients (Mori et al., 1987).

Role of GABA in Epilepsy

It is hypothesized in case of epileptogenesis that reduced inhibition within neuronal networks is the cause of hyper excitability in neurons thus leading to seizures. A reduced GABAA receptors and subunits are observed (Avoli et al., 2005). Observation showed decrease of benzodiazepine binding sites for GABA receptors by using positron emission tomography (PET) (Sata et al., 2002). A study showed that there is different expression of several GABAA receptor subunit mRNA as compared to non epileptic tissue (Palma et al., 2005). The δ subunits of GABA receptor are involved in extra synaptic tonic inhibition and are altered in epilepsy (Peng et al., 2004). Along with GABA receptors, the GABA transporters are also found to be altered in epilepsy and are found to have reduced levels (During et al., 1995). Neuronal peptide Y that plays role in the regulation of food intake is found to have important role in regulation of neuronal excitability (Baraban and Tallent, 2004). A role of gap junctions is also found in synchronizing neuronal networks in epileptic seizure. They allow the flow of electrical signals and small molecules between cells and in this way promote neuronal synchrony (Cannors and Long, 2004). If the gap junctions are blocked, the epileptiform synchronization is decreased and if they are enhanced then increased epileptiform synchronization. Conexxins are proteins that constitute gap junctions. In human epileptic tissue, elevated levels of connexins 43 mRNA have been reported (Aronica et al., 2001). Different changes in gene expression patterns occur in human epileptic hippocampus including cell growth and differentiation, cellular signaling, protein involved in cell matrix interaction and in transcriptional regulation (Becker et al., 2003). GABA when released into the synapse acts on two types of receptors. GABAA that controls entry of chloride ions into the cell and GABAB that increase potassium conductance, decreases calcium ion entry and inhibits the pre-synaptic release of other neurotransmitters.

There are two main types of GABA receptors that are associated with chloride and potassium ionophores. When GABA is bound to its receptor then there is outflow of potassium ions and inflow of chloride ions leading to hyper polarization and inhibitory post synaptic potentials of membranes. This process is essential in preventing neuronal discharge. The GABA blockers such as pencillin and picrotoxin are epileptogenic agents that are used in experimental studies (Avanzini and Franceschetti, 2003). There are other receptors found to be involved in epilepsy as nicotinic acetylcholine receptors. It is a pentameric structure consisting of two α, one β, γ and δ subunits each. Positively charged ions pass through this channel very easily. A mutation was found out in CHRNA4 that codes for α4 subunit of nicotinic acetylcholine receptor, determining the genetic cause of human epilepsy (Steinlein et al., 1995). There are mutations found in CHRNB2 that code for β2 subunits are also associated with genetic causes of disease (Gambardella, 2000).

Alterations in expression and composition of GABAA receptor subunit in the course of epilepsy is well studied in human and animal models. More of a work done on animal models demonstrates changes in inhibitory functions of extrasynaptic GABAA, having contribution towards epileptogenesis. A mutation observed in GABAA receptor γ2 subunit R43Q is involved to impair assembly and cell surface expression of GABAA receptors. This mutation cause increased cortical excitability. The molecular structure of GABAA receptor is heterogenous and their unique trafficking, function, localization and differential expression underscore their complex regulation (Fritschy, 2008)

Role of Glutamate in Epilepsy

The most widespread amino acid in the brain having numerous functions is glutamate. It acts as detoxifying agent for ammonia in brain. Its most important role is as a primary excitatory neurotransmitter (Mayer and Westbrook, 1987). It is synthesized from aspartate, glutamine or glucose. It is stored in synaptic vessels and as a neurotransmitter its extracellular levels must be maintained at controlled level. Uptake of extracellular glutamate is done by sodium dependent glutamate transporters found on neurons and also on astrocytes which are involved in glutamate uptake at the synapse. Inside the astrocyte, it is converted to non polar glutamine and pass freely to neurons. Inside the neurons, it is converted back to glutamine to replenish the neurotransmitter pool (Pfrieger and Barres, 1996). On the neuronal membranes are located receptors for glutamate on which when it binds cause a conformational change and starts a signal transduction cascade in neurons. There are two types of receptors, ionotropic receptors that depolarize the neurons and metabotropic receptors that modulate synaptic transmission (Dingledine et al., 1999).

There are three types of ionotropic glutamate receptors as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainite (KA) and N-methyl-D-aspartic acid receptor (NMDA). These are postsynaptic ligand gated channels and have different gene types. AMPA comprised of various heteromeric configurations of GluR1-GluR4 subunits. KA is comprised of combinations of subunits with two distinct gene families, GluR5-GluR7 and KAI-KAZ families (Dingledine et al., 1999). NMDA is comprised of NRI gene family with varied combinations of NR2A-NR2D subunits (Sucher et al., 1996). As there are three different ionotropic glutamate receptor subtypes and all contributing differently to the excitatory effects of glutamate in CNS (DeLorenzo et al., 2005).

There are 8 types of G protein-coupled metabotropic glutamate receptors (mGluR1-mGluR8). They are found on both pre and postsynaptic membranes and have different classes. Class 1 mGluRs are mGluR1-mGluR5 and are coupled to phospholipase C activation. Class 2 mGluRs are mGluR2-mGluR3 which inhibits adenylate cyclase activity. The rest belong to class3 and also inhibit adenylate cyclase activity but to a lesser extent. They all modulate synaptic transmission in CNS (Conn and Pinn, 1997).

Role of Ca in Epilepsy

The injury to brain that causes neuronal death and the brain damage has a common molecular mechanism by increasing the extracellular glutamate concentration (Tymianski, 1996). With increase in glutamate concentration, there is increased stimulation of glutamate receptor and also increase in concentration of free intracellular calcium with over stimulation of signaling calcium pathways leading to neuronal death (Choi, 1988). Calcium is the major signaling molecule in neurons. The calcium hypothesis of epileptogenesis states that the calcium affect on neuronal function lies on a process involving one extreme that is characterized by brief and controlled calcium loads of normal function, another extreme that is characterized by irreversible calcium loads and neuronal death and a middle ground characterized by prolonged but reversible elevation in calcium that initiate pathological plasticity changes leading to epilepsy development and increase in calcium is responsible for persistence of chronic epilepsy. This hypothesis suggests that after an injury, the surviving neurons with respect to extended calcium exposure are responsible for development and maintenance of epilepsy. This calcium hypothesis suggests three phases as after an injury calcium levels are raised in neurons but not that much to cause cell death and in second phase called the latency phase, these elevated levels initiate second messenger effects producing long lasting plasticity changes and in last phase called chronic epilepsy phase, these elevated levels maintain the chronic epilepsy (DeLorenzo et al., 2005). Elevated calcium levels are responsible for altering GABA receptor recycling thus altering neuronal excitability (Blair et al., 2004) and other effects involve altered gene transcription, neurogenesis, protein expression and turnover, neuronal sprouting and other processes as well (Delorenzo and Morris, 1999).

Genetic and Molecular Basis of Epilepsy

There is a common characteristic found among different types of epilepsies as the neuronal excitability and synchronicity, irrespective of their pathophysiology. Most of the epilepsies are idiopathic but some are found to have abnormal cellular discharges associated with various causative factors such as oxygen deprivation, infection, tumors, trauma and metabolic dearrangemts (Engelborghs et al., 2000). The disorders of neuronal migration are found to be the major cause of developmental disorders leading to epilepsies. These neuronal migrations lead to conditions like agyria, pachygyria and neuronal heterotropia in sub-cortical white matter and these alterations for epileptogenic foci thus causing hyper excitability of cortical networks (Chevassus et al., 1999) and in some cases excitatory glutamate receptors are increased and inhibitory GABA receptors are decreased leading to hyper excitability and epilepsy (Jacobs et al., 1999). Epilepsy with genetic background has their contributions in the etiology of epilepsy and is found in 40 % of patients suffering from the disease (Gardiner, 2000). The studies done in animal models of absence epilepsy suggest a genetic data showing involvement of multiple genes as one gene showed its involvement in being epileptic or not while other genes determine duration and number of epileptic seizures (Renier and Coenen, 2000). One type of epilepsy called autosomal dominant partial epilepsy with auditory feature is characterized by auditory hellucinations and found to be linked to chromosome 10q22-24 (Winamer et al., 2000). Generalized epilepsy with febrile seizure type 1 is caused by point mutation in β1 subunit of voltage gated sodium channel (Wallace et al., 1998) while type 2 is caused by point mutation in α1 subunit (Escayg et al., 2000). Cells in human neo cortical slices are maintained in vitro and their fundamental electrophysiological properties and their patterns of repetitive firing have been characterized by the use of intracellular recordings. These methods are being widely used. These readings and those recorded in animal models show same readings. This reflects the presence of persistence and fast sodium currents and several potassium outward currents and a hyper polarization activated inward conductance (Vreugdenhil et al., 1998).

Epilepsy is a complex disease that has its multiple etiologies. The idiopathic epilepsies have found to have Mendelian inheritance. Many families with certain number of individuals having epilepsy were found to have molecular gene defects. There may be single gene or multiple gene inheritance for epilepsy (Guerrini et al., 2003). Idiopathic epilepsies are those whose etiology is unknown. There are generalize idiopathic epilepsies which are found to be associated with inheritance of single gene called idiopathic generalized epilepsies with simple inheritance and with inheritance of multiple genes are called idiopathic generalized epilepsies with complex inheritance (Berkovic and Scheffer, 2001). Several studies have undergone to locate the common locus for idiopathic generalized epilepsies. One study revealed the loci to be located on chromosome 18 (Durner et al., 2001) while other study provide evidence for loci on chromosome 2q36, 3q26 and 14q23 (Sander et al., 2000). A mutation found out in α1 subunit of GABA receptor (GABRA1), give the example of idiopathic generalized epilepsy with single gene inheritance (Cossette et al, 2002). The main inhibitory neurotransmitter of human is GABA and is a ligand gated chloride ion channel that gives fast inhibitory synaptic transmission. Thus mutation in the related genes like CLCN2, GABRG2 and GABRA1 provide important cause of epilepsy. As any of dysfunction in GABA and chloride conductance, inhibitory mechanism is disrupted leading to hyper excitability of neurons (McCormick and Contreras, 2001). Mutations observed in β1, α2 and α1 voltage gated sodium channel subunit genes and in γ2 subunit GABA receptor subunit genes are found to be involved in generalized epilepsy with febrile seizure plus. There is persistent and prolonged inward sodium current in mutant sodium channel β1 subunit leading to firing of neurons under small depolarization. There is persistent depolarizing sodium current found in SCN1A mutations leading to accelerated recovery from inactivation thus causing hyper excitability in neurons. In case of mutations in GABAA, there is no or greatly reduced inward chloride current amplitude in response to ligand GABA resulting in hyper excitability of neurons (Guerrini et al., 2003). Benign familial conversions are found to be associated with mutations in potassium channel genes KCNQ3 and KCNQ2. In vitro studies revealed that these mutations showed reduction in amplitude of potassium currents that result in hyper excitability of neurons (Singh et al., 1998). Mutations observed in α4 and β2 subunit of the neuronal nicotinic acetylcholine receptor genes CHRNA4 and CHRNB2 are found to be associated with nocturnal frontal lobe epilepsy (De Fusco et al., 2002).

Idiopathic epilepsies are those whose cause is unknown and occur in the absence of other brain abnormalities (Frazen, 2000) while the acquired epilepsy is associated with previous neurological insult (Hauser and Hesdorffer, 1990). Lot of work is going on in the field of molecular biology and genetics to find out the causes of these idiopathic epilepsies and some of them are related to the identification of cell migration abnormalities and certain gene mutations. However, majority of idiopathic cases are unresolved (DeLorenzo et al., 2005). There are studies that suggest the increased production of inflammatory cytokines in association with epileptic seizures. Interleukin 1 beta (IL-1β) is found to be pro-convulsant and neurotoxic while interleukin-1 receptor antagonist (IL-1Ra) is anti-convulsant and neuro-protective. IL-6 appears to be more pro-convulsant (Alapirtti et al., 2009). Most of the epilepsy genes associated with Mendelian inheritance encodes ion channels showing a common result that genetically altered channel function lower seizure threshold. However, two human epilepsy genes are found not to be altered to ion channels. These are MASS1 and LGI1 genes (Owuor et al., 2009).


Over the last few decades, improvement and advancement in the neurobiological investigations have revealed a number of possible causes of a disease that was considered sacred in the past. These investigations done on cellular and molecular basis has helped the neuroscientist to understand in detail the mechanisms underlying the disease. Most of the studies are done on animal models as there are certain limitations while doing on human models but the knowledge has been utilized fully to counteract the most prevalent neurological disease. A lot of work is still in progress.