This is the second module in our series on seizures and epilepsy.
And as you recall from the first module, we delved into the properties of the EEG.
In this module, I'd like to cover three main areas.
First, the properties of individual neurons during a seizure.
Secondly, the factors that can alter the excitability of neurons and
neuronal networks.
And finally, a initial discussion on the causes of epilepsy.
Now, as you recall from the previous module, we ended by taking a look at
an EEG that was recorded while a patient was having a seizure.
And we observed the fact that during the seizure, there is electrical activity
recorded from the EEG that has the properties of very high amplitude, or
high voltage, as well as synchronization,
depicted here by this spiking like activity.
So now let's try to understand what's going on
at a more microscopic level if you will.
Of course, when people observe that the cortex was capable of giving rise to
these large amplitude spiking like activity, It was just a matter of
time before scientists were able to take electrodes and actually probe the cortex
directly to try to determine what was going on at this deeper level.
So, let's explore the nature of this high amplitude spiking activity at
a deeper level.
Well, it was just a matter of time before scientists were able to develop more and
more sophisticated recording techniques.
For example, extracellular recordings allow one to place an electrode into
the region of the cortex shown here, and measure the activity of nearby neurons,
and this represents the type of activity that was recorded
while the experimental preparation was having seizure activity.
And you, as you can see, the cell, or
nearby cells We're giving rise to this high amplitude spiking activity.
Well, with time, there was the development of intracellular recording,
where electrodes were placed directly into the cell, and these recordings represent,
then, the activity of an individual neuron that's in a network that's
undergoing a seizure.
And as you can see there are these periodic bursts of activity.
Let's blow up the time scale here a little bit of one of these discharges, and
as you can see each of these discharges actually represent a series or
a train of bursts of activity.
Now by manipulating the experimental preparation,
it was possible to begin to dissect apart what the various molecular, or
ionic contributions are to this type of electrical discharge.
And what was discovered was that, first of all,
the initiation of this activity began with the release of glutamate,
acting on a post-synaptic ampa receptor, or glutamate responsive receptor.
This leads to the influx of calcium which then,
because of the changes in the depolarization of the cell,
unblocks the NMVA receptor which is also responsive to glutamate.
This then leads to a voltage dependent calcium channel to open up,
which leads to the influx of calcium.
And so if you take a look at this wave, and depict it in yellow.
This wave actually represents a long calcium mediated depolarization.
So there's this envelope of depolarization that's occurring in the cell.
That's mediated by calcium.
As the cell depolarizes,
this then leads to the creation of a series of action potentials.
So each one of these spikes actually is an action potential.
Or a train.
Then, with time, a GABA receptor is stimulated, and
that leads to then relative, or the beginning of hyperpolarization and
similarly a voltage dependent potassium channel also causes hyperpolarization,
and you get a return to the baseline.
This, this signature of a seizure,
this activity of an individual neuron that exists within a seizure network
is referred to as a Paroxysmal Depolarization Shift or PDS.
So when you think about seizure activity in the cortex.
And one thinks about what's going on at the individual cellular level.
I want you to understand that these individual cells are undergoing a PDS.
They are giving off trains of action potentials and of course the EEG spike
that we saw on the EEG, these don't represent individual action potentials.
These are population spikes.
This is spiking activity that represents the activity of many,
many different, hundreds and thousands of cells at the same time.
But each one of those individual cells is undergoing these trains of
action potentials.
With this information you now should be able to understand the definition of
a seizure.
And a seizure is a paroxysmal derangement of cerebral function due to uncontrolled,
excessive discharges from an aggregate of neurons.
So, just imagine, here's a sea of neurons in the cortex.
Each one of them is undergoing a PDS.
Now they, they're not gonna be having the PDS at exactly the same time.
But if these are occurring in a relatively constricted time period,
You can understand why the EEG would be picking up
a relative population spike of all the cells occurring at the same time.
So the key thing about a seizure is that there is both hyperexcitability,
that is these PDSs with trains of action potentials.
And hypersynchronization.
That is a large group of the neurons are firing at relatively the same time.
And this, this is really, this is as simple as it gets.
It's, this is really what happens during a seizure,
hyperexcitability and hypersynchronization.
Alright, so, now that we understand what's going on at the network and
the cellular level during a seizure.
Let's consider some of the factors that could cause a network to
become hyper-excitable or
hyper-synchronized Because ultimately at least many forms of seizures are thought
to result from an imbalance between excitation and inhibition.
So, in order to explore this I want you to think along with me.
What are the various factors that can affect the excitability of a neuron or
a neuronal network?
And to begin this thought experience, here I've drawn in just a prototypical neuron,
right, with its cell body, dendritic tree, and its axon.
So, just think for a moment.
Here's a neuron.
Without thinking about any of the other connections in the circuit,
just the neuron itself.
What are the various characteristics of a neuron that if
altered could result in increased excitability?
What are some of those factors?
What are the molecules that exist in a cell?
What are the processes that exist in a cell,
that if you could modulate in one way or another, would increase excitability?
So, as you start thinking about this, I think you will find that it's actually
fairly easy to come up with a giant list of things that could be changed.
For example, what if we altered the ion flux through a sodium channel?
That made it easier for sodium to flow into the cell.
That would result in an increased excitability,
what if decreased the ion flux through the potassium channel?
That would have the same thing.
What if we placed more glutamate receptors in the dendritic tree?
So that the release of glutamate caused a larger number or
more excitability as a result of EPSPs, and so forth.
So there are, literally, there are dozens,
if not hundreds of ways that you could alter the properties of the neuron itself.
To lead it to be more hyper excitable.
Well, that's just the neuron.
What about the neuron sitting in its network?
Here's a neighboring neuron.
Here's input from inter neurons.
Here's a neuron with it's axon that synapsing in
the proximal of this neuron.dendritic tree of this neuon.
How could alterations in the network result in increased excitability of
this cell?
Well, again, if you just think through this, there are just so
many, so many ways this could change.
You could alter the amount of release of the excitatory,
inhibitory neurotransmitter here at this dendritic synapse.
Another example would be modulation of
actually the physical location of this axon.
For example, if this is an excitatory interneuron, and
the axon has moved farther away from the soma,
then actually the relative contribution of excitation is gonna be less.
If the synaptic contact is more distal from the soma,
than proximal, and so forth.
And finally, let's not forget that it's not just neurons that contribute to
the excitability of the network.
There are also a number of other non-neuronal cells.
For example, the astrocyte, which has many properties which control
network excitability such as its modulation of the ionic concentration
In the extracellular space, the metabolism and the production of glutamate,
depolarization of astrocytes themselves and so forth.
So again, this thought experiment is really meant for
you to just think through the hundreds and
hundreds of different ways that network excitability can be modulated.
So, now, let's turn to definitions again.
And we'll start with epilepsy.
So, epilepsy is a term that refers to
a condition in which a patient has a tendency towards recurrent seizures.
So, if an individual has an,
if an individual has a single seizure, that doesn't make the diagnosis of
epilepsy Epilepsy is when a person has a tendency for recurrent seizures.
So there's something that's been altered in the person's brain that leads it to
have a proclivity towards a recurrence of seizure events.
Epileptogenesis is the sequence of events that turns a normal neuronal network into
a hyperexcitable network.
Now, here's just a brief list of the causes of epilepsy.
And we'll delve into this a little bit more in a subsequent module.
But I just wanted you to get a general look at some of the different causes.
So there's brain injury, so,
traumatic brain injury or a stroke affecting a brain tissue.
Tumors can lead to seizures and epilepsy.
There are genetic causes of epilepsy.
There are developmental abnormalities that either occur because of
a genetic predisposition or are acquired, typically in utero.
Infections can cause seizures and
epilepsy, and a whole variety of metabolic derangements can as well.
So I'm gonna just go through a couple examples of causes of
seizures in epilepsy to emphasize how this can actually occur.
So, here is the chemical structure of a molecule called domoic acid,
or domoate Now, the reason that domoate is very interesting is that in the 1980s,
there was an exposure of a group of individuals who
were up in the region of Prince Edward Island.
Who were eating mussesl which turned out to be contaminated by an organisim called
N pungens, and this particular organism produces this molecule domoic acid.
The molecule turns out to be a poison because the people who
ingested this poison developed coma and encephalopathy.
And many of them actually had very, very severe seizures or status epilepticus.
Most of the individuals with the more severe intoxication actually died, but
a few of them went on to develop long term seizure disorders or epilepsy.
And what's very interesting about this particular intoxication is
that domoic happens to be an analogue of the molecule glutamate.
So, we just referred to glutamate, you'll remember that
glutamate is the most important excitatory amino acid in the brain.
And this domoate,
ingestion was essentially an example of glutamate toxicity in humans.
And the this excitotoxicity caused a injury
diffusely in the brain including here in the human hippocampus.
And it appeared to have caused damage of neuronal network properties that lead
to permanent hyper-excitability in the people who went on to develop epilepsy.
So, here's an example of an intoxication leading to seizures and epilepsy.
Just as an aside,
there are two other rather dramatic examples of this type of toxicity.
Here's a California sea lion.
It turns out in 1998, there was a particularly notable algae bloom that
contained the same organism I mentioned before, N pungens and domoic acid.
And there were about 400 sea lions that developed seizures and
encephalopathy, many of which died.
Also, you may or may not know about the Alfred Hitchcock movie, the Birds.
Which featured this attack by these crazy birds and
it turns out to be Capitola California, down near Santa Cruz.
And this is actually a real occurance, I think it happened in the 1960s,
when these birds were contaminated with the same algae and
domoate and they went crazy with encephalopathy and attacked the town.
Here's another example of an alteration in a network leading to epilepsy.
These are, these are slides taken from the rat hippocampus, and
just to orient you a bit.
Here's a major cell layer called the Dentate Granule Cell Layer and
here's another cell layer, the pyramidal cells and you can see
a whole bunch of other cells here in this region called the hilus and outside.
What I want you to do is look really really carefully at
this upper left versus lower right panel.
Can you see any difference between the two?
You have to look really carefully.
And I'll help you.
I'm gonna highlight some of the cells in red.
And if you now look, you see, see all these cells here?
Are there the same number in this region here?
No.
In fact it's really difficult to find any of these plump larger cells in
this region.
This region called the hilus.
Now the only difference between these two preps, is that this is a control rat, and
this rat one week previously had a 25
millisecond percussion injury on the surface of the cortex.
Actually, you know, many, many millimeters away from this.
Just a single percussion injury while it was under anesthesia,
and then it recovered, and one week later, this is the difference.
So, that, that model of traumatic brain injury led to relative
loss of these selectively vulnerable neurons in the hilus.
And these animals went on to develop hyper excitability, and seizures.
Now, to understand, what the network defect may have
been in these animals, I've drawn this cartoon.
So here we have a dentate granule cell, shown in red.
Here it's sitting in the granule cell layer.
And it's axon is projecting out towards the pyramidal cell layer over here.
And its dendritic tree is going up in this region.
And here's input, coming from, in this case it would be the entorhinal cortex,
for example, with a positive excitatory synapse at the dendrite.
Which would, if sufficient, would lead to an action potential of going out
towards CA3 Now, also in this network, are two inter-neurons.
This is an excitatory neuron that leads to excitation of
the neighboring inter-neuron, which is an inhibitory inter-neuron.
And, as you can see, this is an example of feedback inhibition, right.
If this cell, the granule cell,
discharges, it sends the action potential to CA3.
But it also excites this excitatory inter-neuron, which excites this
inhibitory inter-neuron, which then causes relative inhibition of the same cell, this
is actually a pattern of network function that's seen throughout the nervous system.
feedback inhibition.
Now in various forms of injury,
including the traumatic brain injury that I just showed you.
It's been observed that there is this selective vulnerability of certain
populations of inter neurons and you can now imagine that if this form of injury
leads to a loss of this excitatory inter neuron this would actually lead
to a decrease In the inhibition elicited by this inhibitory interneuron,
rendering the overall circuit more hyperexcitable.
So that's one example of increased excitability.
Another thing that happens is with the loss of this interneuron, the axon can
actually rewire, and grow, and make synapses on neighboring excitatory cells.
And, again, thinking this through, here is an excitatory cell.
You now have this rewired excitatory synapse that is going to
excite neighboring cells,
again rendering the overall excitability of the network, Increased.
So, this is just one of many hypotheses.
Most of this actually has not been proven to be the actual basis of
network excitability leading to seizures.
But it gives you an example of one of the mechanisms of, or a couple of
the mechanisms of epileptogenesis So,let me finish this module with one final
example of a cause of seizures and epilepsy and that is mutations in genes.
Arguably one of the most exciting aspects of
epilepsy research over the last 20 to 25 years has been the discovery of now many,
many dozens of gene mutations that are the basis of epilepsy in humans.
This is just one example of an early finding.
This was the discovery of the mutation in a potassium channel that
is the basis of a certain syndrome of neonatal human epilepsy.
And, like many of these early discoveries, these had been based on the identification
of these large families in which epilepsy clearly runs through the family.
You can see many affected members here.
And by sequencing these individuals, these investigators were
able to identify a particular five base insertion, if you can see
this series here AG CCCT has actually been inserted
into this part of the sequence GCCCT and this result in a change
in the protein coding from tyrosine, aspartate, valine, methionine to cystine,
proline, threonine, threonine, and this turns out to be a stop codon.
So now, this is a potassium channel sub unit that has been truncated, and
further studies have indicated that this truncation leads to dysfunction of
the potassium channel in a way that caused increased excitability.
This potassium channel mutation turns out to be part of a larger class of
mutations that have been discovered in epilepsy that have been referred to
as channelopathies And this cartoon just gives an example of the many different
ion channels that exist both in the pre-synaptic and
the post-synaptic space and mutations in essentially all of these.
The sodium channel pre-synaptically, the sodium channel
post-synaptically, cholinergic receptors in the central nervous system,
potassium channels, GABA receptors and calcium channels.
There are other classes of molecules that are also affected in various forms of
epilepsy but the channelopathies represent the predominant form.
In this module we've covered the nature of individual neurons and
network activity during a seizure.
We've explored some of the factors that control the excitability of neurons and
networks and we've talked about some of the causes of epilepsy.
So with that as a background,
in the next module we'll talk about the classification of seizures.
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