Download Molecular and Cellular aspects of a Sacred Disease `Epilepsy`

Molecular and Cellular aspects of a Sacred Disease
‘Epilepsy’
Abstract
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.
Introduction
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 heterooligomeric 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-5methyl-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.
Channel
Gene
Protein
Voltage Gated
Sodium channel
SCN1A
Type1 α1 subunit
SCN1B
Type1 β1 subunit
SCN2A
Type2 α1 subunit
Calcium channel
CACNA1A
P/Q-Type α1 subunit
CACNB4
CACNA1H
T- Type1 α1 subunit
Potassium channel
KCNA1
Kv 1.1
KCNQ2
M-channel
KCNQ3
KCNMA1
BK channel
Chloride channel
CLCN2
CLC-2
Ligand Gated
Acetylcholine receptor
CHRNB2
β2 subunit
CHRNA4
α1 subunit
GABA receptor
GABRG2
γ2 subunit
GABRA1
α1 subunit
GABRD
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-3hydroxy-5-methyl-4-isoxazolepropionate (AMPA), kainite (KA) and N-methylD-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 neuroprotective. 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).
Conclusion
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.