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
