Temporals a by a Epilepsy
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Transcript of Temporals a by a Epilepsy
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Temporal lobe epilepsy
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Overview
1. What is it? What does it look like? 2. Methods of experimentation
3. Neurobiology of TLE
A. Neurotransmitters/Receptors Glutamate/GABA/Kainate/Neuropeptide Y
B. Metabotropic Receptors
C. Protein Transporters
D. Pathologies and Volumetric deficits
4. Medication and Surgery
5. Concluding remarks
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What is TLE?
Temporal lobe epilepsyis recurrent seizureactivity originating inthe temporal lobe.
Focal (partial)
Simple partial
Complex Partial
Generalized Tonic
Clonic
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Symptoms of TLE
Seizures-usually complex partial
Usually duration is from 1-2 minutes
Auras
Motionless staring
Anxiety
Emergent past memories
Spiritual/Religious experience 1.5% of population worldwide
20% intractable
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Methods
Kindling-A reduction in the threshold for activityresulting in a seizure which is caused by repeatedseizure activity.
Status Epilepticus- Status Epilepticus is when thebrain is in a state of continuing seizure. Clinically, a
person will not regain consciousness in betweenseizures. (Status Epilepticus and Kindling are both induced experimentally
using either electrodes or drugs such as Kainic acid and pilocarpine)
EEG
PET
MRI and CT
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MRI scans of TLE
http://img.medscape.com/fullsize/migrated/editorial/journalcme/2008/18803/sellner.fig1.jpg
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EEG of TLE
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Neurotransmitters, their Receptors
and Relevance
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Glutamate Receptors and Subunits
AMPA-(GluR1, 2, 3, and 4)
Kainate-(GluR5, 6 and 7, and KA1 and 2)
NMDA-(NR1, NR2A, 2B, 2C and 2D)
Variations of specific subunits exist withinsubclasses of the receptors. The subunit signatureof a receptor is what ultimately determines its
biochemical and physical properties such as channelstructure, ion permeability, and gating kinetics.
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Glutamate Subunits and TLE
Kainate receptors containing the GluR6 unitcontribute to postsynaptic seizure occurrence.
This takes place in pyramidal neurons in the CA3
section of the Hippocampus Receptors containing the GluR7 unit are thought to
inhibit the onset of seizures.
Less seizure activity is found in lab mice that have an
increased expression of the NR2 subunit.
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The NMDA Receptor
Over activation of the NMDA receptor can lead toseizure activity particularly in the amygdala.
NMDA receptor antagonists increase threshold forexperimental seizure induction. Less effective inexisting seizures. (McNamara et al.,1988)
MK-801 is a good example of an antagonist
MK-801 structure
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NMDA Receptor
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MK-801
Binding Site
MK-801 and its Binding Site
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NMDA (cont)
MK-801 has been shown to inhibit the potentiation of circuitswhich could lead to long term seizure activity.
Potentiation of connections can be induced from kindling. This
is in part caused by the activation of the NMDA receptor.
In the supraoptic nucleus and adjacent limbic areas, there is anincrease in expression of the NR2B subunit and a decrease in
the NR2D subunit. For glutamate receptors, subunit
expression is more susceptible than actual modulation in
function to influence from seizure activity.
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AMPA Receptor
Seems to have stronginvolvement in seizure expressionin the Amygdala.
AMPA receptor antagonists canreduce this tendency.
Works only in the presence of the
drug. After withdrawal, goes backto normal.
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AMPA and NMDA in conjunction
It is commonly held that AMPA receptorsare critical for the induction of seizure
discharges, while NMDA receptors arecritical for inducing the trans-synapticalterations that underlie permanent kindledepileptogenesis. (Morimoto, 2004 17)
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Reorganization
The activation of NMDA receptors from a seizuremay drive potentiation that will result instrengthened seizure circuitry.
This may contribute to recurring epileptic activityafter the initial seizure.
Although potentiation is often present in seizurecircuits, epilepsy can also persist in the absence of
such potentiation.
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AMPA and NMDA Receptors
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Gamma-Amino Butyric Acid
(GABA) Receptors Subtypes
GABA-A: fast inhibition by bringing Chlorideions into the cell.
GABA-B: Presynaptic autoreceptors. Slowaction via K+ conduction
GABA-A is believed to be more involved.
Agonists- alleviate seizures
Antagonists-exacerbate seizures
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GABA Receptors (cont)
Beta subunits determine channel properties and GABAaffinity.
Modulations Upregulation of GABA-A receptors in Dentate Gyrus in
response to seizure activity. An increase in binding sites is evident in the
hippocampus and amygdala.
Decrease in actual binding occurring
Receptor density increase of 34-40%-(Nusser et al.
1998) This was found through tracking the Beta 2 and3 subunits in dentate granule cells.
Enlarged synaptic terminals
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GABA-A Receptor
GABA-B Receptor
Integral Membrane
Protein (Hydrophobic ends
exposed)
Peripheral
Membrane
Protein
(Hydrophilic ends
exposed)
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Neuropeptide Y
NPY is a 36 amino acid peptide found in GABA containinginterneurons.
Brain Derived Neurotropic Factor (BDNF) regulates NPY expression
Activation of Y2 receptors by NPY has inhibitory effect ontransmission of glutamate.
mRNA transcription for NPY is increased in hippocampus cells as aresponse to experimental kindling.
Seizure activity modulates Y receptors making them more sensitive tobinding.
In rats, an increase in expression of the gene for the synthesis of NPYcaused a decrease of 65% in the ability to lower threshold
experimentally. Is the brain compensating?
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Metabotropic Receptors and
Protein Transporters
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mGluR
mGluR is the class of Glutamate metabotropicreceptors.
Groups II and III of mGluR are presynapticautoreceptors and are believed to be involved in
irregular release of glutamate. Little is known about the effects of kindling; however,
agonist drugs of these receptors have an inhibitingeffect on seizure activity.
A decrease in sensitivity of these agonists my indicatea loss of mGluR-mediated hyperpolarization.-(Holmes, et al. 1996)
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Protein Transporters
A glutamate transporter protein uses reuptakemechanisms in order to modify the amount of excessglutamate in the synapse.
EAAT=Excitatory Amino Acid Transporter
Subtypes (EATT1-5) unique in composition and action
Experimental inhibition causes concentrations to be toodense resulting in neurodegeneration from excitotoxicity.
Implications: Malfunction of these mechanisms result innot only cell death but also chronic epilepsy.
GABA has its own protein transporter EAAC1 whose
inhibition would cause similar hyperactivity. GABAsynthesis is decreased.
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Pathologies and Volume Deficits
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Pathologies: Ammons Horn
Sclerosis (AHS) Present in 2/3 of TLE patients
Characterized by heavy cell loss in theCA1, CA3, and CA4 sections of thehippocampus.
The CA2 area and granule cells of thedentate gyrus is not as affected asother areas.
Astroglyosis- astrocyte increase due tocell loss
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Dentate Gyrus
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Dentate Gyrus
Experimental kindling may actually inhibit granulecell firing in the DG in the short term.
Despite excitatory potentials, the threshold forfiring is actually increased temporarily.
May be why granule cells are on average lessdamaged than pyramidal cells in thehippocampus.
Hippocampus-lowest seizure threshold
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Pyramidal
Cells
Axonal
Sprouting
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Volume Abnormalities
There are deficits in corticalvolume within the temporallobe for a person sufferingfrom TLE.
There may be volumedeficits in the lobe contralateral to the side thatexperiences the seizures.
Cortical Lobe volumedeficits correlate with theamount of cell death in
each area of thehippocampus.
Atrophied
Hippocampus
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Medication and
Pharmacoresistance
Examples of Antiepileptic drugs: Phenobarbital
Dilantin
Tegretol Neurotin
Many antiepileptic medications act as GABA agonists
Pharmacoresistance occurs in advanced stages ofTemporal Lobe epilepsy. Medication ceases to be
effective. Surgery is often the next step.
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Temporal Lobe Surgery
Only considered when medications have failed to alleviatesymptoms or have lost their potency.
Seizure Locus-removal is a very common procedure.
Temporal lobe resection
Successful in reducing or eliminating seizures about 70-90%of the time.
Multiple subpial transection-when focus is not operable oris out of reach.
Study in 2000-seizure disappearance-surgery 64%,
medication alone 8% Surgery is not always successful-Intractable
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Resection
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Fin