L2 - Molecular determinants of the epilepsies

Question 1

What is epilepsy?

Answer 1

Chronic neurological disorder characterised by spontaneous recurrent seizures

Question 2

True or false

Epilepsy has no age, racial, social, gender or geographical boundaries

Answer 2

true

Question 3

The cause of epilepsy is…

Answer 3

unknown in appox half of those suffering - genetic and acquired

Question 4

epilepsy is thought to occur as a result of …

Answer 4

an imbalance between excitatory (glutamatergic) and inhibiry (GABA) neurotransmission - which usually work together to maintain neuronal homeostasis

Question 5

over __% of patients don’t respond to current drug treatments

Answer 5

30%

Question 6

Describe focal seizures:

Answer 6

Start in one region of the brain - but can then spread

usually result from an acquired brain insult

have underlying structural brain pathology

good candidates for surgery

Question 7

Describe generalised seizures:

Answer 7

Start in both hemispheres of the brain simultaneously

Mostly genetic causes

No underlying structural brain pathology

Question 8

Generalised non-convulsive seizures are usually ___ episodes of staring with unresponsiveness. You have have ___ per day. The have a ____ onset. Can be provolked by _______

Answer 8

Generalised non-convulsive seizures are usually brief episodes of staring with unresponsiveness. You have have hundreds per day. The have a sudden onset. Can be provolked by hyperventilation

Question 9

True or false

Generalised non-convulsive seizures are common in childhood

Answer 9

true

Question 10

The cause of Generalised non-convulsive seizures are unknown

Answer 10

true

but there is a strong genetic component - but more than one gene involved

Question 11

Descibe the GAERS model

Answer 11

Genetic absense epilepsy rats from strasbourg (GAERS)

100% develop seizures by 4 months

NEC is the control strain - no seizures

polygenic: more than one gene contributing

most widely used animal model - many of the same features as human epilepsy

Question 12

Absense seizures result from abnormal, ________ ________ activity

Answer 12

hypersynchronous thalamocortical activity

Question 13

What makes up the thalamocortical circuit?

Answer 13

Somatosensory cortex

Ventrobasal nucleus of the thalamus

reticular nucleus of the thalamus

Two modes of firing:
awake –> tonic
sleep –> oscillatory

Question 14

During absense seizures the brains switches to the ____ sleep moide in the thalamocortical circuit, while the person is still awake

Answer 14

Sleep –> oscillatory

Question 15

What are the multifactorial molecular causes of genetic generalised epilepsy?

Answer 15

High/Low voltage activated Ca2+ channels

AMPA receptors

Stargazin and TARPS

GABA(a) receptors

K+ channels

voltage gated Na+ channels

Question 16

true or false

Mutations in human Ca3.2 t-type calcium channel have been found in patients with genetic generalised epilepsy

Answer 16

true

we need to investigate how human mutations are effect calcium channel function - but study is hard in human patients

Question 17

true or false

anti-epileptic drugs work in all patients

Answer 17

false

some people they dont due to the mutations they carry

Question 18

Do GAERS have mutations n the same genes as humans with genetic generalised epilepsy (GGE)?

Answer 18

yes

Ca 3.2 mutation Ca2_ channels - changes arginine to proline

we know GAERS is polygenic tho, but it IS homozygous for this mutation

Question 19

Is the Ca 3.2 mutation highly conserved?

Answer 19

Yes - has a high homology in mammals

Question 20

The GAERS mouse has one copy of the R1584P mutation in Ca 3.2 mutation Ca2+ channels gene

Answer 20

false

two copies (PP)

exhibits spontaneous absence seizures

Question 21

By looking at heterozygous genes of the R1584P mutation we can assess…

Answer 21

the extent to which the Ca 3.2 mutation

Showed that is correlates with the epileptic phenotyle

Question 22

True or false

R1584 Ca 3.2 mutation affects seziure duration

Answer 22

false

Question 23

GGE is polygenic. How can we investigate the role of R1584 Ca 3.2 mutation in isolation?

Answer 23

Ca3.2 transgenic mouse

can be switched on/off in different cell types

Question 24

What is stargazin?

Answer 24

ubiquitously expressed in the brain

expression enriched in synaptic plasma membranes

Stabilises AMPA receptors

Question 25

Describe the features of the stargazin mouse

Answer 25

Mutation in stargazin gene

Has an epileptic, ataxic and head tossing phenotype

Has reduced stargazin mRNA and undetectable protein levels

Question 26

True or false

GAERS has a mutation in the stargazin gene

Answer 26

False

Question 27

What do AMPA receptors do?

Answer 27

mediate the actions of excitatory neurotransmitter, glutamate

Question 28

How does Stargazin modulate the AMPA receptor function?

Answer 28

AMPA receptors won’t be stable without stargazin

Question 29

Gaers have ______ stargazin mRNA expression in the ________cortex _____but not ______ the onset of seizures

Answer 29

Gaers have increased stargazin mRNA expression inthe somatosensory cortex after but not before the onset of seizures

It is a consequence of the seizures

Question 30

AMPA receptor protein is ______ specifially at the plasma membrane in gaers

Answer 30

increased

Question 31

INcreased stargazin leads to ….

Answer 31

hyperexcitability

Question 32

How can we investigate if this increase in stargazin and AMPA receptor expresion is causative of epilepsy?

Answer 32

Small interfering RNA or viral knockdown/overexpression

in an non-epileptic animal increase stargazin and/or AMPA receptor expression and see if the animal has absense seizures

Question 33

name some of the ion channels implicated in the pathophysiology of GGE

Answer 33

T-type calcium channels,
AMPA receptors
Stargazin

Question 34

True or false

mutations in humans with GGE are also present in animal models of GGE ( GAERS)

Answer 34

True