L2 - Molecular determinants of the epilepsies Flashcards Preview

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Flashcards in L2 - Molecular determinants of the epilepsies Deck (34):
1

What is epilepsy?

Chronic neurological disorder characterised by spontaneous recurrent seizures

2

True or false

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

true

3

The cause of epilepsy is...

unknown in appox half of those suffering - genetic and acquired

4

epilepsy is thought to occur as a result of ...

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

5

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

30%

6

Describe focal seizures:

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

7

Describe generalised seizures:

Start in both hemispheres of the brain simultaneously

Mostly genetic causes

No underlying structural brain pathology

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 _______

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

9

True or false

Generalised non-convulsive seizures are common in childhood

true

10

The cause of Generalised non-convulsive seizures are unknown

true

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

11

Descibe the GAERS model

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

12

Absense seizures result from abnormal, ________ ________ activity

hypersynchronous thalamocortical activity

13

What makes up the thalamocortical circuit?

Somatosensory cortex

Ventrobasal nucleus of the thalamus

reticular nucleus of the thalamus

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

14

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

Sleep --> oscillatory

15

What are the multifactorial molecular causes of genetic generalised epilepsy?

High/Low voltage activated Ca2+ channels

AMPA receptors

Stargazin and TARPS

GABA(a) receptors

K+ channels

voltage gated Na+ channels

16

true or false

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

true

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

17

true or false

anti-epileptic drugs work in all patients

false

some people they dont due to the mutations they carry

18

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

yes

Ca 3.2 mutation Ca2_ channels - changes arginine to proline

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

19

Is the Ca 3.2 mutation highly conserved?

Yes - has a high homology in mammals

20

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

false

two copies (PP)

exhibits spontaneous absence seizures

21

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

the extent to which the Ca 3.2 mutation

Showed that is correlates with the epileptic phenotyle

22

True or false

R1584 Ca 3.2 mutation affects seziure duration

false

23

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

Ca3.2 transgenic mouse

can be switched on/off in different cell types

24

What is stargazin?

ubiquitously expressed in the brain

expression enriched in synaptic plasma membranes

Stabilises AMPA receptors

25

Describe the features of the stargazin mouse

Mutation in stargazin gene

Has an epileptic, ataxic and head tossing phenotype

Has reduced stargazin mRNA and undetectable protein levels

26

True or false

GAERS has a mutation in the stargazin gene

False

27

What do AMPA receptors do?

mediate the actions of excitatory neurotransmitter, glutamate

28

How does Stargazin modulate the AMPA receptor function?

AMPA receptors won't be stable without stargazin

29

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

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

It is a consequence of the seizures

30

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

increased

31

INcreased stargazin leads to ....

hyperexcitability

32

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

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

33

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

T-type calcium channels,
AMPA receptors
Stargazin

34

True or false

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

True