Thalamocortical Physiology (childhood epilepsy) - Restrepo/Park

Question 1

What cells contain T-type Ca channels (of those involved in the thalamic relay circuit?)

Answer 1

The thalamic relay neurons.

Question 2

What is the frequency of the delta (δ) wave? When does it show up during sleep?

Answer 2

~3 Hz.

Phase 4 sleep (Slow wave)

Question 3

Describe the circuit between the thalamic relay neuron, the reticular cell, and the cerebral cortex in terms of inhibitory/excitatory.

Answer 3

The thalamic relay neuron synapses on the the cerebral cortex (excitatory connection) and the cortex synapses onto the thalamic relay neuron (also an excitatory connection). Both the cortex and the thalamic relay neuron synapse onto the reticular neuron. (Excitatory connections).

The reticular neuron synapses onto the thalamic relay neuron (INHIBITORY).

The sensory system also synapses onto the thalamic relay neuron.

[Figure 3 pg. 5]

Question 4

Describe the thalamic neurons in the awake state as compared to the asleep state (Resting potential, frequency of AP, inhibition by reticular cell)

Answer 4

Awake: Thalamic relay neurons are depolarized (-55mV), fire rapid APs, UNinhibited by the thalamic reticular nuclei.

Asleep: Thalamic relay neurons are hyperpolarized (-80mV), fire APs at 3Hz, inhibited by the thalamic reticular nuclei (GABA).

Question 5

Why does the thalamic neuron fire rapid APs while awake, and slow (3Hz) APs while asleep?

Answer 5

The inactivation gate of the T-Type Ca channel is OPENED in the hyperpolarized state (below -55mV), and closed in the depolarized state.

When the gate is open, you get the Ca-based 3Hz slow oscillations. When closed, you get the NaV based rapid APs.

Inhibition by the reticular cell (GABA) influences the resting membrane potential (ie UNinhibited resting potential is -55mV, INhibited potential is -80mV)

Question 6

Mice with no T-type Ca channels. Can they be induced to have “Absence-like seizures”?

Answer 6

No.

Question 7

Mice with T-type Ca channels in which the inactivation gate does not close. Can they have “Absence-like seizures”?

Answer 7

Yes.

Question 8

What drugs inhibit the T-type Ca channel, and are used to treat “Absence-like seizures”?

Answer 8

Ethosuximide and valproic acid.

Question 9

How can an EEG read thalamic activity? Isn’t the thalamus too deep in the brain for superficial electrodes to record?

Answer 9

Yes. But, the thalamic relay circuit connects to the cortex.

[However, as you will see in this lecture the thalamus affects activity of cortical neurons through axonal connectivity between the thalamus and the cortex]

Question 10

What is the state of the T-type Ca channel inactivation gate during slow wave sleep?

Answer 10

Open.

Question 11

What mutation in the T-type Ca channel could lead to Absence epilepsy, in which delta waveforms are seen?

Answer 11

A mutation in the inactivation gate in which it fails to close above -55mV. You would then get seizures while awake.

Question 12

GABAergic neurons in the reticular nucleus synapse onto the thalamic relay neuron, inhibiting and depolarizing it during sleep.

What cells stimulate these neurons, causing them to stop firing and allow the animal to wake up?

Answer 12

Cholinergic cells in the reticular formation.

[When an animal is asleep, stimulation of cholinergic neurons in the reticular activating system results in awakening of the animal and interruption of slow waves in the EEG.Stimulation of these cholinergic neurons releases acetylcholine in the thalamus]

Question 13

Concept: Children whose seizures start early in life are (more/less) likely to outgrow the condition as they age?

Answer 13

More likely.

Question 14

What are the three epilepsy syndromes mentioned in lecture?

Answer 14

Childhood Absence Epilepsy
Juvenile Absence Epilepsy
Juvenile Myoclonic Epilepsy

Question 15

A 4 y/o girl who suffers frequent, small seizures (blinks, lip movements) which are precipitated by hyperventilation likely suffers from which seizure syndrome?

What is the prognosis

Answer 15

Childhood Absence Epilepsy

80% no longer have seizures in adulthood.

There are some sequelae, however (less likely to complete college, for example).

Question 16

A boy has onset of seizures at 12 y/o. The seizures are less frequent, and of a longer duration. He likely suffers from?

Answer 16

Juvenile Absence Epilepsy

Question 17

A 15 y/o child has Generalized Tonic Clonic seizures and myoclonic seizures surrounding periods of sleep. These events are relatively infrequent. What syndrome is likely at play?

Answer 17

Juvenile Myoclonic Epilepsy

Question 18

What clinical signs indicate and Absence seizure?

Answer 18

“staring off”

Also may have small movements of the mouth, eyelids. They are NOT RESPONSIVE during these epiodes and they CANNOT RECALL things that were said to them.

Question 19

Describe the genetics of Juvenile Absence seizure syndromes (broad terms).

Answer 19

Probably heterogeneous, but underlying risk factor is genetic as evidenced by high concordance between twins/siblings/family members.

Question 20

In Childhood Absence Epilepsy what would an EEG show prior to and during an episode?

Answer 20

Normal background. During the event, will see slow depolarizations (2-3 Hz).

3Hz “spike and wave” pattern is the characteristic phrasing.

Question 21

Is atypical Absence epilepsy associated with a better or worse prognosis?

Answer 21

Worse.

Question 22

What is the best pharmacologic treatment for Childhood Absence Epilepsy?

2nd?

Answer 22

Ethosuximide. Blocks the T-type Ca channels.

2nd: Valproic Acid