The Science of Seizures: From Neurotransmitters to Medication Targets in Epilepsy
Chapter 1: Neurological Pathways

[Music] 

Hi, I’m Dr. Selim Benbadis. 

This chapterized video reviews the science of seizures, from the neurological pathways disrupted in epilepsy to targets for pharmacologic treatment. 

In this first chapter we’ll explore what actually happens in the brain during a seizure. 

Seizure initiation is characterized by 2 events: high-frequency bursts of neuronal firing, or action potentials, and hypersynchronization of a population of neurons. 

Seizures can result from a disruption in the balance between excitation and inhibition in the brain, due to a combination of increased neuronal recruitment, electrophysiological changes within neurons, enhanced connectivity between neurons, enhanced excitatory transmission, and a failure of inhibitory mechanisms. 

To better understand the neuronal dynamics that give rise to this disruption in excitatory and inhibitory balance, let’s review some basic principles about how neurons communicate. 

At rest, the inside of a neuron is more negatively charged than the outside. 

When the neuron is activated or depolarized, voltage-gated sodium channels open. Positively charged sodium ions enter the cell, further depolarizing the membrane. 

If the depolarization reaches a threshold, the neuron fires an action potential. 

The action potential travels down the axon, causing voltage-gated calcium channels to open at the presynaptic terminal and allowing calcium ions to enter the cell. 

Calcium, through interactions with proteins at the synaptic terminal, triggers the fusion of neurotransmitter-containing vesicles to the synaptic cleft. This triggers neurotransmitter release into the synaptic cleft, allowing it to passively diffuse and bind to receptors on the postsynaptic neuron. 

Glutamate is the primary neurotransmitter responsible for excitatory neuronal signaling in the brain. 

When glutamate is released by the presynaptic neuron, it binds to ionotropic glutamate receptors on the postsynaptic neuron. This rapidly depolarizes the postsynaptic neuron, causing an excitatory effect. 

Three ionotropic glutamate receptor subtypes have been identified: 

• AMPA receptors, which are permeable to potassium and sodium when activated;
• kainate receptors, which are also permeable to potassium and sodium;
• and NMDA receptors, which are permeable to potassium, sodium, and calcium.

GABA is the key inhibitory neurotransmitter. 

When GABA is released by inhibitory neurons, it exerts a rapid inhibitory effect by binding ionotropic GABAA receptors on the postsynaptic neuron. 

When GABAA receptors are activated, negatively charged chloride ions can pass through and enter the neuron. 

This chloride influx hyperpolarizes the neuron, decreasing its probability of firing. 

In a healthy brain, activity levels are balanced. This is, in part, accomplished by the interplay between inhibitory and excitatory neurotransmission. 

Inhibitory neurons inhibit the activity of the neurons they contact. 

Conversely, excitatory neurons primarily activate the neurons they contact. Their role is to transmit information to neurons in other brain areas. 

A disruption in this neurotransmitter balance is thought to play a role in seizures and epilepsy. 

Preclinical and human studies of seizures and epilepsy suggest that the balance between glutamate and GABA signaling is disrupted, shifting in the direction of neuronal excitation. 

Studies in both preclinical animal models and human patients have revealed a role for glutamate-activated AMPA receptors in seizures and epilepsy. 

Quantitative in vitro receptor autoradiography has shown increased AMPA receptor density in tissue resected from 10 patients with pharmacoresistant focal epilepsy compared to 10 nonepileptic controls. 

Note that autoradiography is an imaging technique used to characterize distribution of a radiolabeled substance throughout the body. 

In this study, investigators used specific radiolabeled ligands to measure binding to NMDAR, AMPAR, KAR, and GABAAR in neocortical tissue, providing a map of receptor density. 

As you can see, this study did not find a significant difference in binding density of NMDA receptors, kainate receptors, or GABAA receptors between patients with epilepsy and nonepileptic controls. 

Thanks for watching this chapter. Check out Chapter 2 on this website to learn about seizure etiologies and their proposed biophysical mechanisms. 

To learn about an antiseizure medication option with a unique mechanism of action, please watch Chapter 3 on this website.