L2 - Molecular determinants of the epilepsies Flashcards
What is epilepsy?
Chronic neurological disorder characterised by spontaneous recurrent seizures
True or false
Epilepsy has no age, racial, social, gender or geographical boundaries
true
The cause of epilepsy is…
unknown in appox half of those suffering - genetic and acquired
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
over __% of patients don’t respond to current drug treatments
30%
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
Describe generalised seizures:
Start in both hemispheres of the brain simultaneously
Mostly genetic causes
No underlying structural brain pathology
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
True or false
Generalised non-convulsive seizures are common in childhood
true
The cause of Generalised non-convulsive seizures are unknown
true
but there is a strong genetic component - but more than one gene involved
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
Absense seizures result from abnormal, ________ ________ activity
hypersynchronous thalamocortical activity
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
During absense seizures the brains switches to the ____ sleep moide in the thalamocortical circuit, while the person is still awake
Sleep –> oscillatory
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
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
true or false
anti-epileptic drugs work in all patients
false
some people they dont due to the mutations they carry
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
Is the Ca 3.2 mutation highly conserved?
Yes - has a high homology in mammals
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
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
True or false
R1584 Ca 3.2 mutation affects seziure duration
false
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
What is stargazin?
ubiquitously expressed in the brain
expression enriched in synaptic plasma membranes
Stabilises AMPA receptors
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
True or false
GAERS has a mutation in the stargazin gene
False
What do AMPA receptors do?
mediate the actions of excitatory neurotransmitter, glutamate
How does Stargazin modulate the AMPA receptor function?
AMPA receptors won’t be stable without stargazin
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
AMPA receptor protein is ______ specifially at the plasma membrane in gaers
increased
INcreased stargazin leads to ….
hyperexcitability
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
name some of the ion channels implicated in the pathophysiology of GGE
T-type calcium channels,
AMPA receptors
Stargazin
True or false
mutations in humans with GGE are also present in animal models of GGE ( GAERS)
True
