Temporal Lobe Epilepsy

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Temporal Lobe Epilepsy

• Bryan Callahan
• Psychology 760
• Dr. Jennifer Thomas

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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 epilepsy is recurrent seizure
  activity originating in the temporal lobe.
• Focal (partial)
• Simple partial
• Complex Partial
• Generalized
• Tonic
• Clonic

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What causes it?

• Head Trauma
• Heart Attack
• Stroke
• Genetics
• Alcohol withdrawal
• Brain tumors
• Infection
• Experimentally induced
• Sleep deprivation
• Photosensitivity
• Other neurological diseases
• Ex. Meningitis
• Idiopathic

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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
  activity resulting in a seizure which is caused
  by repeated seizure activity.
• Status Epilepticus- Status Epilepticus is when
  the brain is in a state of continuing seizure.
  Clinically, a person will not regain
  consciousness in between seizures.
• (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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Decreased Glucose metabolism during cessation
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fMRI
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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 within
  subclasses of the receptors. The subunit
  signature of a receptor is what ultimately
  determines its biochemical and physical
  properties such as channel structure, ion
  permeability, and gating kinetics.

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Glutamate Subunits and TLE

• Kainate receptors containing the GluR6 unit
  contribute 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 to
  seizure activity particularly in the amygdala.
• NMDA receptor antagonists increase threshold for
  experimental seizure induction. Less effective
  in existing 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 and its Binding Site
MK-801 Binding Site
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NMDA (cont)

• MK-801 has been shown to inhibit the potentiation
  of circuits which 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 an increase 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 strong involvement in seizure
  expression in the Amygdala.
• AMPA receptor antagonists can reduce this
  tendency.
• Works only in the presence of the drug. After
  withdrawal, goes back to normal.

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AMPA and NMDA in conjunction

• It is commonly held that AMPA receptors are
  critical for the induction of seizure discharges,
  while NMDA receptors are critical for inducing
  the trans-synaptic alterations that underlie
  permanent kindled epileptogenesis. (Morimoto,
  2004 17)

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Reorganization

• The activation of NMDA receptors from a seizure
  may drive potentiation that will result in
  strengthened seizure circuitry.
• This may contribute to recurring epileptic
  activity after the initial seizure.
• Although potentiation is often present in seizure
  circuits, 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 Chloride ions
  into the cell.
• GABA-B Presynaptic autoreceptors. Slow action
  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
  GABA affinity.
• 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 and 3 subunits in dentate granule cells.
• Enlarged synaptic terminals

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Peripheral Membrane Protein (Hydrophilic ends
exposed)
GABA-A Receptor
GABA-B Receptor
Integral Membrane Protein (Hydrophobic ends
exposed)
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Neuropeptide Y

• NPY is a 36 amino acid peptide found in GABA
  containing interneurons.
• Brain Derived Neurotropic Factor (BDNF) regulates
  NPY expression
• Activation of Y2 receptors by NPY has inhibitory
  effect on transmission of glutamate.
• mRNA transcription for NPY is increased in
  hippocampus cells as a response to experimental
  kindling.
• Seizure activity modulates Y receptors making
  them more sensitive to binding.
• In rats, an increase in expression of the gene
  for the synthesis of NPY caused 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 metabotropic
  receptors.
• Groups II and III of mGluR are presynaptic
  autoreceptors 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
  inhibiting effect on seizure activity.
• A decrease in sensitivity of these agonists my
  indicate a loss of mGluR-mediated
  hyperpolarization.-(Holmes, et al. 1996)

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Protein Transporters

• A glutamate transporter protein uses reuptake
  mechanisms in order to modify the amount of
  excess glutamate in the synapse.
• EAATExcitatory Amino Acid Transporter
• Subtypes (EATT1-5) unique in composition and
  action
• Experimental inhibition causes concentrations to
  be too dense resulting in neurodegeneration from
  excitotoxicity.
• Implications Malfunction of these mechanisms
  result in not only cell death but also chronic
  epilepsy.
• GABA has its own protein transporter EAAC1 whose
  inhibition would cause similar hyperactivity.
  GABA synthesis 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 the CA1, CA3,
  and CA4 sections of the hippocampus.
• The CA2 area and granule cells of the dentate
  gyrus is not as affected as other areas.
• Astroglyosis- astrocyte increase due to cell loss

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Dentate Gyrus
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Dentate Gyrus

• Experimental kindling may actually inhibit
  granule cell firing in the DG in the short term.
• Despite excitatory potentials, the threshold for
  firing is actually increased temporarily.
• May be why granule cells are on average less
  damaged than pyramidal cells in the hippocampus.
• Hippocampus-lowest seizure threshold

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Axonal Sprouting
Pyramidal Cells
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Volume Abnormalities

• There are deficits in cortical volume within the
  temporal lobe for a person suffering from TLE.
• There may be volume deficits in the lobe contra
  lateral to the side that experiences the
  seizures.
• Cortical Lobe volume deficits correlate with the
  amount of cell death in each area of the
  hippocampus.

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 of
  Temporal 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
  alleviate symptoms 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 or is 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