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Neurobiology of Epileptog Neurobiology 2018.pdf · PDF fileEpilepsia. 1997. Excitatory Center Inhibitory surround Basket cells ... •Potentiation EPSP in stimulated pathway •Long

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Text of Neurobiology of Epileptog Neurobiology 2018.pdf · PDF fileEpilepsia. 1997. Excitatory...

Neurobiology of Epileptogenesis

Michael C. Smith, MDDirector, Rush Epilepsy Center

Professor and Senior Attending NeurologistRush University Medical Center

Chicago, IL

Lothman EW. Epilepsy: Models, Mechanisms, and Concepts. 1993.

Molecular, Synaptic, and Cellular Effects of Seizures

hours-to-daysweeks-months-years

seconds-to-minutes

SEIZURE

Ca++Enzyme Activity

Adenosine

K+

Intracellular

Extracellular

Presynaptic Element(Axon Terminals)

Postsynaptic Element(Receptors/Channels)

Presynaptic-Postsynaptic Functional Unit

Glutamate Excitation

GABA Inhibition

Glia

Neurons

Local Circuit

Projection Circuit

Facilitation

PTPLTP

Synaptogenesis

Necrosis

Neuron Loss

Apoptosis

Gene Expression

NerveGrowth Factors

Axon Proliferation, Growth

12 3

4

KainateReceptors

BZD Receptors

5

Gliosis

Excitation > Inhibition Imbalance

Disconnection Between Regions

Net

wo

rk M

ilieu

Cel

lula

r M

ilieu

Syn

apti

c M

ilieu

Mo

lecu

lar

Mili

eu

Basic Mechanisms of Seizures

Neuronal short-circuit - PDS

Paroxysmal Depolarization Shift

Neuronal synchronization

Gap junctions, ephaptic coupling, electrical fields, ionic concentrations

Transition from interictal to ictus

Failure of inhibition, excessive excitation

Paroxysmal Depolarization Shift

Paroxysmal Depolarization Shift (PDS) is described in both experimental animal models of epilepsy and in human tissue obtained in epilepsy surgery

Intracellular expression of epileptic spike

Well-characterized with micro-electrode studies

Paroxysmal Depolarization Shift

Paroxysmal depolarizationshift

o

Vm

Vth

Vrest

-70mV

TIME Voltagedependent K

+effluxCa+2

dependent

200msec

Na+

infl

ux

Ca+

2in

flu

x

Paroxysmal Depolarization Shift

Pathophysiology of PDS

Abnormal ionic conductance (Na+/Ca++)

Due to increased number of ionic channels

Excessive response to normal input

Due to excessive excitatory input

Giant EPSP (excitatory post-synaptic potential)

Probably a combination of both

PDS Origin of Interictal Spike

Wong PK, et al. Prog Brain Res. 1984.

Intracellular recording

Extracellular recording

Paroxysmal depolarizing shift

PDS Ionic Conductance

Westbrook G. Principles of Neuroscience. 2000.

A. Interictal PDS within seizure focus B. Basic cortical circuit

Feedback inhibition

Feed-forward inhibition

Epileptic Focus Interplay Between Excitatory and Inhibitory Circuitry

Westbrook G. Principles of Neuroscience. 2000.

Neurobiology of Absence Seizures

Dichter MA. Epilepsia. 1997.

AEEG

Neuron

0-20-40-80

-100

GABA GABA GABA GABA

T-Ca++T-Ca++T-Ca++

1 sec

BCortex

ThalamusT

R

T

R

Re

Nu

Neuronal Synchronization

Poorly understood and difficult to study

Synchronization is necessary to reach the critical mass of neurons to overwhelm normal surround inhibition for transition to ictus

There are multiple mechanisms responsible for neuronal synchronization

Neuronal Synchronization

Neuronal synchronization may occur at dendritic and axonal levels, but not at cell body

Gap junctions on these processes, when blocked, prevent fast ripple potentials that synchronize adjacent neurons

Electrical field effects may synchronize adjacent neurons

Alterations in extracellular space and ionic concentrations affect neuronal excitability and synchronization

Scharfman HE. Curr Neurol Neurosci Rep. 2007.

Interactions Between NMDA Activation, Extracellular Space and Potassium Concentration

Burst AHP

Ephapticcoupling

Depolarization

Spike threshold

NMDA receptor

Cell swelling

Larger [K+] transient duringinterictal burst

NEURONALFIRING

DURINGINTERICTAL

BURSTS

Seizure

ECspace

IPSP

RISE INBASELINE [K+]

Effects of Seizure on Extracellular Space and Ionic Concentration

Lothman EW. Epilepsy: Models, Mechanisms, and Concepts. 1993.

Glial Cell - Role in Generation and Spread of Seizures

Impaired K+ buffering due to reduced gK(IR) in sclerotic epileptic hippocampus

Enhanced expression of astroglial gap junction protein supports hypersynchronization

Enhanced activation of metabotropic glutamate receptors with increased intracellular Ca++

Steinhuser C. Eur J Pharmacol. 2002.

Astrocytic Ionic Regulatory Function

Steinhuser C. Eur J Pharmacol. 2002.

Pathophysiology of Interictal Spike

Dichter MA. Epilepsia. 1997.

Excitatory Center

Inhibitory surround

Basket cells

Interictal dischargeOriginating in temporal lobe

PyramidalCells

Synaptic inhibition insurrounding neurons

DS

Hyperpolarization

Transition to Ictus

Imbalance of excitation and inhibition

Failure of inhibition:

Activity dependent disinhibition

Loss of the after hyperpolarization (AHP)

Loss of surround inhibition

Excessive glutamate stimulation

Positive feedback

Recurrent excitatory feedback circuitry

Staley K. Nat Neurosci. 2015; Scharfman HE. Curr Neurol Neurosci Rep. 2007.

Transition from Interictal State to Ictus

Lothman EW. Epilepsy: Models, Mechanisms, and Concepts. 1993.

Tonic Phase Clonic Phase

Seizure Focus Distant

GABA Desensitization Leading to Inhibitory Failure

Glutamate Neurotransmission

Dichter MA. Epilepsia. 1997.

Excessive Excitation Breaking Down Inhibition

Lothman EW. Epilepsy: Models, Mechanisms, and Concepts. 1993.

Seizure-induced Change in Neuron Function and Structure

An 18-month old male has a 25 minute convulsion followed by R-sided Todds Paralysis. The following may occur:

A. Excitotoxic damage to the dentate gyrus

B. Neuronal reorganization leading to hyperexcitable hippocampus

C. Increased risk of later seizures

D. All of the above

Example of Excitotoxicity in Hippocampus after Status Epilepticus

Brooks-Kayal AR, et al. J Neurosci. 1999; Stasheff SF, et al. Science. 1989; Sharfman HE. Prog Brain Res. 2007.

Important Factors in Epileptogenesis

Alteration/expression/membrane localization in GABAA subunits resulting in changes in phasic/tonic inhibition and response to modulators (BZD/Zn)

Up-regulation of NMDA and AMPA is seen in both models of epileptogenesis and from TLE pathology

Reorganization of neuronal networks

Tauck DL, et al. J Neurosci. 1985; Sutula T, et al. Science. 1988.;Sharfman Prog Brain Res,2007

Synaptic Reorganization Resulting in Hyperexcitability and Epilepsy

Seizures result in neuronal death of the hilar dentate neurons

The hilar dentate neuron is the target of the dentate granule mossy fiber axon

These fibers seek new synaptic contacts, at times, re-innervating themselves resulting in a recurrent positive feedback loop

Holmes MM, et al. Behav Neurosci. 2002.

Hippocampal Reorganization

Sloviter RS, et al. Science. 1989.

Synaptic Reorganization Resulting in Hyperexcitability and Epilepsy

Hyperexcitability is due to the loss of feed forward inhibition due to loss of excitatory input to the inhibitory basket cell

Loss of the inhibitory neurons feedback inhibition

Probably all three mechanisms are involved

Sloviter RS, et al. Science. 1989.

Changes in Synaptic Connectivity in Epilepsy

Sloviter RS. Ann Neurol. 1994.

Hippocampal EpilepsyDentate Gyrus as Gatekeeper

Dentate gyrus

A - Normal circuitry

B -Temporal lobe epilepsy

Dentate gyrus

Hippocampus

Dentate gyrus

Dentate gyrus

Parahippocampal gyrus

Hippocampus

Parahippocampal gyrusBCBC

G

Mossy cell

_ _+ +

+

BC BCG

Mossy cell

_ _+ +

+

Hippocampus

Dentate gyrus

Parahippocampal gyrus

1 2 3

1 2 3

Lothman EW. Epilepsy: Models, Mechanisms, and Concepts. 1993.

Receptor Activation During SeizureTonic-Clonic Electrographic Paroxysm

EEG

Neuron

PrimaryEpileptogenicZone

AMPA

GABA

NMDA

Non-T Ca++

1sec

Zone ofDissemination

0-20-40-60-80

-100

Inflammation in Experimental Models

In many animal models of epilepsy and acute seizures there is up-regulation of inflammation with microglial activation and increased expression of transcription factors and cytokines that help coordinate the inflammatory response

Toll-like receptor (TLR) family upregulated in microglia leading to transcriptional activation of cytokines, chemokines in the MHC class I and II

This contributes to the seizure-related neuronal death and neuronal reorganization seen in hippocampal epilepsies

Zimmer LA, et al. J C

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