Epilepsy is a group of neurological disorders characterized by the occurrence of spontaneous recurrent seizures (1).
Epidemiological studies from the United States, estimate that about 3% of all people living to the age of 80 will be diagnosed with epilepsy(2).
Epilepsy syndromes and seizure types are classified as being either partial (originating from a focal part of one hemisphere) or generalized (with bilateral initiation).
Absence (or petit mal) seizures are a type of non-convulsive, generalized seizure characterized by brief unresponsiveness to environmental stimuli without a loss of postural control. Patients experience a momentary loss of consciousness lasting 3–15 s, which often goes undetected, except for brief staring spells, eyelid flutter, or minor automatisms that are dependent on the duration of the seizure (3).
Patients have no recollection of what occurred during the seizure event (3).
Absence seizures have a sudden onset and offset, occur most commonly during moments of quite wakefulness and do not involve any post-seizure symptoms.
The only diagnostic test for absence seizures is the electroencephalogram. Absence seizures show a characteristic spike and wave pattern on the EEG during the seizure event (ictal period).
These spike and wave discharges are bilateral and synchronous, with a frequency of 3Hz (range 2.5-4Hz) and a duration consistent with the symptomatic loss of consciousness in the patient of around 10s (range 4-20s) (4).
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The inter-ictal (between seizure) EEG shows no abnormalities. Further, absence seizures are often provoked by hyperventilation, and this can be used diagnostically in conjunction with the EEG (3).
Absence seizures are an integral part of many idiopathic generalized epilepsies – so called because they are self-originating or spontaneously occurring (3-5) – including Childhood Absence Epilepsy (CAE) and Juvenile Absence Epilepsy (JAE).
CAE is the most common epilepsy syndrome to affect children; the annual incidence of CAE has been reported to be in the range of 2–8 per 100,000 children under 15–16 years of age,with a prevalence of 2–15% among children with any type of epilepsy(3, 4).
CAE is characterized by very frequent (up to 200 per day) and very brief absence seizures appearing as classical spike and wave discharges on the EEG, and normal intelligence and development (3, 4).
About 30% of patients with CAE also have febrile seizures (4).CAE usually start between 3 and 8 years of age, with a peak incidence around 6-7 years. Approximately 60% of patients show spontaneous remission during adolescence but the remainder frequently develop tonic clonic (or grand mal) seizures in adulthood (3).
No structural lesion of any kind has ever been identified as the substrate of typical absence epilepsies; thus, they are generally regarded as having a multifactorial genetic aetiology (4, 6).
CAE reportedly has a 16-40% positive family history, and a concordance of 70% and 33% in monozygotic twins and first-degree relatives (4).
The pathophysiological mechanism behind absence seizures is believed to involve both cortical hyperexcitability and abnormalities in the thalamocortical circuitry. However, debate continues over whether the origin of absence seizures is in the thalamus or the cortex. We will return to these issues later, but it would valuable to first describe the thalamocortical circuit.
The thalamocortical circuitry includes cerebral cortex, the relay nuclei of the dorsal thalamus and the reticular nucleus of the ventral thalamus (6).
The thalamus is critical in a large number of pathways; all sensory pathways, and many of the anatomical circuits used by the cerebellum and basal ganglia involve thalamic relays(7).
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Most thalamocortical axons terminate in cortical layers III and IV(6).
But given the abundance of cortical interconnections information relaying through the thalamus is also passed to other cortical areas(6).
Reciprocally thalamic relay neurons receive corticothalamic projections from pyramidal cells from layers V and VI of the cortex (2, 6).
Thalamocortical and corticothalamic connections are mainly glutamatergic and excitatory.
The thalamocortical relay neurons also have a strong, reciprocal interaction with GABA-ergic inhibitory neurons in the reticular nucleus of the thalamus. The neurons of the reticular thalamus receive collaterals from both thalamocortical relay axons (part of the reciprocal connection) and corticothalamic axons (6, 8).
Further, reticular neurons also have strong inhibitory connections amongst themselves (2, 9).
Inhibition in the cortex is mediated by local non-pyramidal interneurons, which influence the activity of cortical pyramidal neurons (6).
Cortical interneurons receive both thalamocortical and extrathalamic. See Fig. 1. Also inhibitory cells within the perigenucleate or reticular nucleus.
Thalamocortical neurons have two distinct physiological states: a tonic mode and a burst mode (6, 8, 10, 11).
During states of arousal, the thalamocortical neurons operate in tonic mode and generate, fast, single or trains of action potentials, reflecting the nature of the sensory (or other) stimulus being relayed through the thalamus to the cortex (8, 11).
During states of drowsiness and slow-wave sleep, thalamocortical neurons generate repetitive bursts of action potentials and thalamocortical transmission of sensory input is blocked, as in deep sleep, or pathological states such as coma and seizures (8).
Burst firing is mediated by the activation of a specialized Ca2+ current, known as the low-threshold or, transient Ca2+ (IT) current (11).
This calcium current is mediated by a special type of calcium channel known as the low-voltage activated (LVA) T-type calcium channel(2, 6, 10-14).
This channel is inactivated at standard resting membrane potentials (typically between -60 and -65 mV) but becomes available for activation when the cell is hyperpolarized (at minimum membrane potential negative -73mV) (13, 14).
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Activation of these channels then occurs at membrane positive to approximately -65mV (11).
Above that membrane potential even small depolarizations can then transiently open the channel (thus its name: the LVA T-Type channel) and depolarize the cell, before the T-Type channels once more inactivate (2, 11) . Therefore if the membrane potential is depolarized from a relatively hyperpolarized membrane potential, then the T-Type channels may first activate and then more slowly inactivate, generating a low-threshold Ca2+ spike (11).
These Ca2+ spikes typically last on the order of 100-200ms, and in turn bring the membrane potential positive to threshold (approximately -55mV) for the generation of three to eight fast action potentials that a responsible for the 7-14Hz spindle waves seen during non-REM sleep (2, 11, 15).
However, thalamocortical cells in burst mode, generate not only 7-14Hz sleep spindles – which may be explained by IT – but also rhythmic bursts of action potential in the range of 0.5-4Hz (11).
These intrinsic lower frequency bursts have been explained by the interaction of IT with a hyperpolarization activated cation current Ih, described in thalamocortical neurons (11, 16).
Ih is a mixed Na+ and K+ current that is activated when thalamocortical neurons are hyperpolarized negative to -55mV, and depolarized the neuron back toward the reversal potential of -35mV (11).
Thus the slowly depolarizing Ih current activates the It and generates burst spikes. The interaction between the two currents is best understood in Figure 1.
The GABAergic neurons have firing properties analogous to thalamocortical neurons. They also have two modes of operation: high frequency bursts (at 350-400Hz) during non-REM sleep and a tonic mode of firing during wakefulness (11, 17).
The bursts fired by thalamic reticular neurons have a much longer duration that those fired by thalamocortical neurons (17).
Again, it is believed that these two activity states result from an IT current, the only difference being that voltage dependence of this current is shifted to more positive membrane potentials (11, 18).
Two more differences are of note in thalamic reticular neurons. Firstly an after-hyperpolarization follows the generation of Ca2+ spike bursts in thalamic reticular neurons as a result of Ca2+ activated K+ conductance (IKCA) (11, 18).
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The amplitude and duration of this after-hyperpolarization can be sufficient to remove the inactivation of T-Type channels and result in the generation of an additional Ca2+ burst (11).
IT and IKCA interact in such a way that thalamic reticular cells fire at frequencies of 0.5-12Hz. Secondly, unlike in TC neurons, rhythmic burst firing in thalamic neurons is often followed by a tail of single spike activity (11).
This tail of activity is reported to be generated by Ca2+ activated non-cation current (ICAN).
Hence, thalamic reticular neurons can generate a form of activity that takes the form of burst-burst-burst-tonic firing(11).
See fig 3.
One paradigm of the generation of absence seizures – thalamocortical circuitry promotes rhythmicity –
It has been proposed that the cellular mechanisms underlying the generation of absence seizure may be a perversion of those that generate normal thalamocortical rhythms during sleep. As summarized by Futatsugi: 1. activation of thalamic reticular cells would result in an inhibition of thalamocortical relays via hyperpolarization; 2. this deinactivates T-type channels and activates Ih, which promotes the generation of It and subsequent action potentials; 3) the burst outputs of these thalamocortical relay neurons would excite both thalamic reticular and cortical neurons; 4. the activated nRt neuron might restart the whole cycle (2, 19).
The above posits a subcortical pacemaker as being the essential component in the genesis of absence seizures, and is known as the centrecephalic theory (20).
There are however other paradigms used to explain the genesis of absence seizures. The cortical theory holds that absence seizures are primarily the expression of a cortical abnormality (20).Summarized below is the evidence supporting each of these theories.
Evidence for the cortical theory
As early as 1953 Bennett showed in patients with petit mal seizures that injection of the convulsive drug pentylenetetrazol in the carotid artery supplying the cortex produced generalized spike and wave activity (20).
In contrast such responses were absent when this drug was injected in the vertebral artery, which supplies the diencephalon (midbrain, including thalamus) and brainstem. Subsequent studies found that intravertebral administration attenuated seizure, thus still implicating the thalamus in the pathophysiology but not necessarily the genesis (20).
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Depth recordings in some patients with childhood absence epilepsy (CAE) have found that discharges occurring during a seizure might initially be localized to the frontal cortex, in the neighbourhood of a lesion (20).
Experimental work by Steriade and Amzica demonstrated that cortical neurons displayed time lags between their spike trains, and progressively increased synchrony during the paroxysm (21).
The findings question the validity of not only the centrecephalic theory, but also the common definition of seizures as “suddenly generalized and bilaterally synchronous.”
Thus, over the past decade the cortical theory
Studies on animals where thalamic inputs have been severed (either through pharmacological methods or thalalectomies) are inconclusive. Large lesions
The T-Type Calcium Channel
Rises in intracellular calcium levels are critical in many process including gene expression, synaptic plasticity, neurotransmitter release, activation of calcium dependent enzymes and regulation of neuronal excitability (13, 14).
Though the nervous system expresses many different calcium channels with unique cellular distributions, they are usefully classified into two major categories: low-voltage activated calcium channels (LVA) and high voltage activated calcium channels (HVA) (13).
LVA channels were discovered after the discovery by Eccles – later elucidated and confirmed by Llinas and colleagues – that some neurons show increased excitability in response to hyperpolarizing impulses (22, 23).
Subsequent studies blocking Na+ and K+ channels, and removing Ca2+ from the extracellular solution, led to the suggestion that a new, low-threshold, or low-voltage activated Ca2+ current, mediated by a new type of channel was responsible for this hyperpolarization dependent excitation (14, 22).
A single channel entity, that was more metabolically stabile than HVA channel – i.e. recalcitrant to modulation by neurotransmitters or second messengers – and showed a different pharmacological profile was then identified (22, 24, 25).
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The first HVA calcium channel subunits were successfully cloned in the late 1980s, after purification from skeletal muscle, sequencing and screening of cDNA libraries (26-28).
The adoption of PCR techniques and further homology-based cloning led to the identification of further HVA channel subunits in the early 1990s (28).
However these techniques, dependent on sequence homology, failed to clone LVA channels which have low sequence homology with HVA channels. Breakthroughs came with the development of genetic databases – in particular the databases of expressed sequence tags (EST), the C. elegans genome project and the human genome project (27).
Text-based searches of the Genbank database were undertaken to find new sequences that showed homology with cloned calcium channels (29).
This identified multiple cDNA clones that were unique (30).
Human clone H06096 – first isolated isolated by the LLNL Consortium as part of an effort to identify all messenger RNAs (mRNAs), or expressed sequence tagged (EST) genes – was sequenced as it showed significant sequence homology with the first membrane spanning region of domain III of the carp aIS (26, 29-31) . In spite of its low homology to cloned HVA channels, H06096 had an identifiable pore loop and S4 voltage sensor motif. Using H06096 as a probe to screen human heart and rat brain cDNA libraries identified human a1H and rat a1G in 1998 (29, 30).
GenBank was next searched using the H06096 sequence revealing that it was related to the H06096 was related to the C. elegans sequence found on cosmid C54d2 (14, 26).
Subsequent screening of GenBank using the 3’ end of C54d2 as a probe revealed another human EST – H19230. Low stringency screening of rat brain cDNA libraries using H19230 led to the identification of a third protein A1I (32).
Since then similar methods, often combined with PCR techniques, have led to the cloning of all three T-Type subunits from humans, rats and mice (27, 33-35).
Structure
The principle pore forming unit of both HVA and LVA channels is the a1-subunit. As Khosravani and Zamponi note this subunit contains the key structural moieties that are required for a functional calcium channel, and which is the sole determinant of the calcium channel subtype (13).
Nine different a1 subunits have been identified and fall into three major classes: Cav1, Cav2 and Cav3 (13).
Cav1 encodes different isoforms of L-type channels, Cav2 encodes P/Q, N and R type channels depending on the splice isoform, and the Cav3 family encodes T-Type channels.
The a1 subunit of calcium channels are comprised of four transmembrane domains (denoted I, II, III, IV) that are evolutionarily related to similar motifs found in sodium and potassium channels (13, 36).
Each domain in turn consists of six transmembrane helices (denoted S1-S6) with intracellularly localized NH2 and COOH termini (13).
The fourth transmembrane helix (S4) is considered to form a voltage sensor that modulates channel opening (13, 37).
The reentrant P-loops between S5 and S6 segments are believed to line the pore and determine ion selectivity – divalent cations are preferred to monovalent ones. Though in general there is a high level of conservation in S4 and pore loop regions between HVA and LVA channels, slight differences in the amino acid sequence of the LVA pore loop have been established (14).
The protein is nearly wholly cytoplasmic and domains are linked by cytoplasmic linker regions. The I-II linker region has recently been implicated in forming an inactivation gate in LVA channels, though other regions are also considered important. Work using splice variants of Cav3.1 has suggested that the III-IV linker loop may also be important in determining the gating properties of the channel. The sequence of these linker regions (or linker loops) is poorly conserved between HVA and LVA channels. This corresponds to function for though the linker regions are important in HVA channels for the binding of regulatory subunits, no such association has been documented in vivo for LVA channels (14, 27).
Alternative Splicing
Genes encoding all three T-Type subunits – CACNA1G for Cav3.1, CACNA1H for Cav3.2 and CACNA1I for Cav3.3 can all be alternatively spliced (27, 38-40).
Splicing appears to be regulated in a tissue-specific manner and splicing variants with differing properties may allow neurons to fine tune their bursting properties (27).
Additionally there is evidence that variant transcripts are expressed in developmentally regulated fashion during human brain development (27, 41).
Should be one more reference
Functional analysis of alternatively spliced variants of each of the human T-type channels has demonstrated that alternative spliced isoforms vary (modestly, but significantly) in their voltage-dependence and kinetics (40, 42, 43).
As Zhong et al note however, the effects of the kind of missense mutations found in humans and later characterized in HEK293 cells (44) and the effects of alternative splicing must be considered in conjunction(40).
Missense mutations may not only modify electrophysiological function but may also lead to aberrant patterns of expression of physiological variants, especially if, as found, some of the mutations flank splicing junctions (40).
It is possible too, for feedback mechanisms regulating gene expression to be affected by changes in protein structure caused by alternative splicing(40).
Mutations may differentially affect different splice isoforms as well(40).
These the findings further support the concept that the reported mutations in LVA channel genes can manifest their effects in numerous ways beyond direct biophysical changes (13) . all this is crucial given that Merv’s mutation is not far away from our region of interest.
Auxillary Subunits/Subunit regulation
The fact that recombinant Cav3.1 and Cav3.2 expressed solely as a1 subunits produced currents with similar properties to native T-type channels suggests that ancillary subunits do not substantially affect channel function (22, 27).
This is in sharp contrast to HVA channels where subunit expression is critical in determining channel trafficking and assembly (esp. β subunits) biophysical properties and plasma membrane expression (13, 27, 45).
HVA channels form oligomers comprising of a α1 protein always accompanied by auxiliary β, α2-δ-subunits, and sometimes by auxiliary γ subunits. Not counting splice variants, there are four known types of β subunit protein (β1 to β4), four types of α2-δ protein (α2-δ1, α2-δ2, α2-δ3, α2-δ4,) and eight types of γ proteins (γ1 to γ8)(45).
β proteins are, with rare exceptions, wholly cytoplasmic, while α2-δ and γ are transmembrane proteins.
Two strategies have been used to determine the influence of HVA subunits on LVA channels: 1) antisense oligonucleotides directed against HVA subunits have been introduced into LVA expression systems and 2) LVA channels have been coexpressed with HVA subunits. Lambert et al found that the introduction of antisense oligonucleotides against β subunits in nodosus ganglion neurons, which display both HVA and LVA currents, decreased the current amplitude of high voltage-activated channels and modified their voltage dependence, but had no effect on T-Type current (46).
These results were replicated in a neuroblastoma cell line (47).
Both studies were undertaken before any T-type channels cloned, so their results are not specific for the effects on a particular LVA protein. Subsequent work by Dolphin et al found that coexpression of cloned β subunits has little or no effect on cloned T-type channel activity (48).
This is concordant with the structural differences between HVA and LVA channels in the I-II linker loop.Unlike HVA channels, LVA channels do not contain the full consensus sequence identified to be the binding site for β subunit on the I-II linker loop (26, 48).
This notwithstanding Dubel et al have found coexpression of the β1b subunit increases total and plasma membrane expression in Cav3.3 channels, leading to the suggestion that HVA subunits may stabilize LVA proteins during transport to the membrane with necessarily associating tightly (49).
Similar ambiguity prevails regarding α2-δ subunits. Lacinova first reported an absence of
modulation the Cav3.1 by either α2-δ1 or neuronal specific α2-δ3 (50), but two subsequent studies found that α2-δ1 and α2-δ2 could increase plasma membrane expression and current amplitude in all three T-type channels (48, 49).
The γ subunits appear to have little effect on channel expression but the γ2 subunit has been reported to slow the deactivation of Cav3.3 (51).
In addition γ2, γ4 and γ5 have been reported to accelerate inactivation of Cav3.1 currents and shift steady-state inactivation by -4 mV (14).
Part of the reason for the equivocal results in this field, is that unlike HVA channels, LVA channels are yet to be purified. Where HVA channels subunits were initially identified in purified preparations of skeletal muscle, the in silico methods of LVA cloning have largely precluded this kind of discovery. Wolfe et al recently demonstrated inhibitory in vivo association between Cav3.2 and G-protein βγ subunits (52), but no such work is available concerning in vivo association with HVA auxiliary subunits. This, along with further research clarifying relationships between the various auxiliary subunits and the three T-Type channels is required, especially given that spontaneous mutations in α2-d2, β4, γ2 subunits produce complex phenotypes featuring spike and wave discharges in animal models (45).
Biophysics
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