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Neuroscience > Epilepsy > Flashcards

Epilepsy Flashcards

1
Q

What is epilepsy?

A

A disorder of the CNS characterized by recurrent, sudden, large increases in electrical activity (electrical seizures) that may be localized or generalized

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2
Q

What determines Neuronal output (fire action potential or not)?

A

– Determined by number of excitatory and inhibitory synaptic inputs – Strength of individual inputs
- Integrated response

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3
Q

What can synapse transmitters do?

A

• Synaptic transmitters can:
– Excite neurons – depolarize
- Inhibit neurons – ‘hyperpolarize

• Also can modulate activity ion channels involved in: – Transmitter release (voltage gated calcium channels)
– Controlling membrane excitability (potassium channels)
• Changes frequency/number of action potentials

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4
Q

What is the role of glutamate in the CNS?

A
  • Glutamate – major excitatory transmitter in CNS
  • Mediates most of fast excitatory neurotransmission

– ~70-90% of CNS synapses - glutamatergic

• Principle mediator of sensory information, motor coordination, emotions, cognition (including memory)

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5
Q

Where does glutamate act?

A

Acts on specific receptors – Ionotropic receptors (ion channels)

Metabotropic receptors (G protein coupled receptors)

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6
Q

What does aspartate do in the CNS?

A

– mediates transmission at a small number of central synapses

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7
Q

How is the brains glutamate supply maintained?

A

– Non-essential amino acids – Do not cross blood-brain barrier not supplied by circulation

– Synthesized in brain from metabolism of glucose

  • Also from glutamine synthesized by astrocytes
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8
Q

What happens to glutamate after it has been released into the synapse?

A

Released glutamate taken up primarily by astrocytes

Glutamine Synthase – Converted into glutamine by glutamine synthase

– Glutamine transported out of astrocytes

– Glutamine uptake by neurons (transporter)

– Converted back to glutamate by the enzyme, glutaminase

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9
Q

Which molecule of the TCA cycle is converted into glutamate?

A

Alpha-Ketoglutarate

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10
Q

How do synaptic vesicles accumulate glutamate?

A

– electrical gradient created by different concentrations of H+
across vesicle membrane (i.e. inside vesicle and in cytoplasm)

• Vesicle positive potential with respect to cytoplasm

– Electrical potential gradient generated by vesicle ATP proton (H+) pump

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11
Q

What is the synaptic vesicular concentration of glutamate?

A

• Vesicle concentration >20mM

– 1,000 – 2,000 molecules per vesicle

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12
Q

Describe the sequence of events of Release and reuptake of synaptic glutamate

A

• Action potential in pre-synaptic neuron
– Depolarizes the pre-synaptic terminal
– Depolarization opens voltage gated calcium channels
– Calcium flows into terminal
– High local concentration of intracellular Ca2+
– Triggers exocytosis of synaptic vesicle contents ok

• Glutamate diffuses across synaptic cleft
– Interacts with specific receptors
– Multiple receptor types

• Reuptake of glutamate (and aspartate)
– Excitatory Amino Acid Transporters (EAATs)
– Reduces the extracellular concentration
– Terminates transmitter action

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13
Q

How does glutamate reuptake work?

A

• Glutamate transporters drive uptake through EAAT
– Co-transport of (2-3) Na+ and H+ into the cell
– Counter-transport of K+

• Most transporters located on
– Glial cells (astrocytes)
– Post-synaptic neurons (lesser extent)

Post-synaptic Exocytosis
• Some glutamate may diffuse to act at adjacent synapses

(• Km for glutamate ~low micromolar
– Keeps extracellular concentration low
• ~15,000 – 20,000 transporters per synaptic bouton –
Effective uptake process)

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14
Q

Outline the different types of glutamate receptors?

A

• Two large families of receptors

• Ionotropic receptors
– ion channels Ionotropic
– Binding site located on channel
– Agonist binding promotes channel opening
– Role in fast synaptic transmission
– 3 classes:
• NMDA (N-methyl-D-aspartate) receptors AMPA
• AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors
• Kainate receptors (kainate found in some seaweeds)
• Names based on ability of these drugs to selectively activate channels
• Glutamate is the natural transmitter at all receptors

• Metabotropic receptors
– G protein coupled receptors
– Modulatory effects on neuronal function and synaptic transmission

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15
Q

See page 12 of glutamate excitatory lecture for a table?

A

-

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16
Q

Three agonists that work at AMPA receptors?

An antagonist?

A

Glutamate
AMPA
Kainate

CNQX

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17
Q

Three agonists that work at NMDA receptors?

An antagonist?

A

Glutamate
Aspartate
NMDA

D-AP5, D-APV, MK-801
Ketamine
Phencyclidine

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18
Q

How are glutamate receptors distributed in the brain?

A

• AMPA & NMDA receptors often co-localise at functional excitatory synapses
– Ratios at individual synapses varies greatly
– Some can contain only one sub-type
– Some can contain only one sub-type

• Only small number of kainate receptors in most CNS regions

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19
Q

What is the structure of ionotropic glutamate receptors?

A
  • Each subunit has 3 transmembrane spanning domains
  • Large extracellular N-terminus
  • Receptors made up of 4 subunits
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20
Q

What type of excitatory transmission are AMPA receptors involved in?

A

• AMPA receptors
- fast excitatory synaptic transmission
– Fast synaptic current
– Fast decay due to relatively low affinity (Kd ~200nM)

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21
Q

What type of excitatory transmission are NMDA receptors involved in?

A

• NMDA receptors
Fast excitatory neurotransmission
– Slower onset than AMPA
– Slower decay (up to several hundred msecs) – why?
– Higher affinity glutamate binding (Kd ~ 5nM)
- glutamate Stays on receptor even after synaptic clearance of glutamate - goes between open and closed state

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22
Q

What a AMPA receptors assembled of?
What is the relative synaptic current speed?
To what are they permeable?

A
  • Assembled from GluR1-4 – Tetramers
  • Fast synaptic current

• All permeable to Na+ & K+ (some also Ca2+-permeable)
– Depolarizes towards reversal potential, ~0mV
- Activation depolarizes neuron
– Activation depolarizes neuron

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23
Q

To what ions are NMDA receptors permeable?

A

• NMDA receptors are permeable to Na+, K+ and Ca2+

– Ca influx can also activate 2nd messenger systems and Ca dependent enzymes

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24
Q

What does the slower action of the NMDA receptor allow?

A

• Slower action of NMDA receptors
– Provides mechanism for spatial & temporal summation

– Also voltage sensitive
• At membrane potentials

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25
Q

What is meant by ‘NMDA receptors act as ‘co-incidence’ detectors (i.e. several inputs)’?

A

– Needs repetitive or multiple excitatory inputs from other AMPA receptors -depolarize the neuron and relieve the Mg2+ block depolarize the neuron and relieve the Mg block

– Act to sense activity of many independent synaptic inputs on same neurone

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26
Q

What is the structure of an NMDA receptor?

A

• Tetramers

– 2 NR1 subunits plus 2 NR2 subunits

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27
Q

What factors are require to make an NMDA receptor function?

A

– Glutamate binds to the NR2 subunit

– Binding of glycine ( or D-serine) to a site on NR1 – (not to be confused with inhibitory glycine receptors)

  • Glycine concentration in brain saturating for some sub-types
  • Potential site for drugs to act : drugs that prevent glycine binding will inhibit NMDA receptorsa
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28
Q

What drugs block NMDA receptors?

A

Phencyclidine

Ketamine

Dextromethorphan

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29
Q

What effects do NMDA receptor antagonists have in small concentrations?

A

• Psychotomimetic
− Cognitive defects
− Hallucinations
− Delusions

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30
Q

What effects do NMDA receptor antagonists have in higher concentrations?

A

• Dissociative anaesthetics
− Sensory dissociation
− Analgesia
- amnesia

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31
Q

What is the the NMDA antagonist Dextromethorphan used as?

A

Cough suppressant

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32
Q

What type of drug is ketamine and what is it used for?

A

NMDA receptor antagonist

Ketamine: anaesthetic/analgesic
-pediatric anaesthesia, emergency surgery, (usually with sedative drug e.g. Diazepam). Suppresses breathing less than most other anaesthetics and increases cardiac output.

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33
Q

How many Metabotropic Glutamate receptors are there?

A
  • 8 receptors known mGluR1 8

* 7 transmembrane G-protein coupled receptors

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34
Q

Are metobotropic glutamate receptors made up of subunits?

A

• Not formed of subunits – One molecule = one receptor

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35
Q

How are metobotropic glutamate receptors grouped?

A

• Grouped into 3 groups according to:
– Amino acid sequence homology
– Agonist pharmacology
– Signal transduction pathways

– Group I, II & III

36
Q

Where are metobotropic glutamate receptors located?

A

Located in different regions of CNS
– Pre-synaptic
– Post-synaptic

37
Q

Which metobotropic glutamate receptors are in Group I, and what is the pathway that they activate?

A 
Group I:
 mGluR1, mGluR5 
- Activates Phospholipase C 
- production of IP3 and diacylglycerol (DAG) 
• IP3 - Ca2+ release 
-increase intracellular Ca2+ concentration
• DAG activates Protein Kinase C 
 protein phosphorylation 
Modifies ion channel activity

(Beta-gamma complex dissociated can interact with ion channels directly)

38
Q

Which metobotropic glutamate receptors are in Groups II and III and what is the pathway they are in?

A

Group II:
mGluR2, mGluR3

Group III:
mGluR4,
mGluR6-8

  • Inhibits adenylate cyclase
  • decrease cAMP levels
  • Modifies ion channel activity
    (Beta-gamma complex dissociated can interact with ion channels directly)
39
Q

What are the modulators effects of pre-synaptic metobotropic glutamate receptors?

A

– Inhibit voltage-gated Ca channels – reduce transmitter release • Primarily group II & III receptors

– Glutamatergic terminals (inhibitory autoreceptors)

– Terminals that release other transmitters

40
Q

What are the modulators effects of post-synaptic metobotropic glutamate receptors?

A

• Post-synaptic effects - variable
– Inhibit some K+ channels
– increase excitability

– Increase activity of some K+ channels – decrease excitability

– Effects depend on cell type involved

41
Q

View second to last page of glutamate excitability lecture

A

-

42
Q

What do you you know about the link between calcium influx and excitotoxicity?

A

• Many ionotropic glutamate receptors are permeable calcium – Greatly increased glutamate release seen with a seizure or in ischaemia/reperfusion with e.g. stroke
– Intense receptor activity

• Large Ca2 influx – Overwhelms normal Ca2+ buffering & sequestration into intracellular organelles

  • Increased intracellular Ca2+ concentration – Normally used as a signalling pathway e.g. activate some enzymes
  • Protein kinase C, Phospholipase C –

BUT large Ca2+ increase
• Activates Ca2+-dependent enzymes that cleave proteins (proteases)
• Generates damaging – Lysophospholipids - compromise membrane integrity – Oxidative stress (free radicals)

• Leads to cell death
(Why they want an NMDA antagonist - Limit the effects of stroke
- would have to be given v. Soon after event though)

43
Q

What is the major inhibitory neurotransmitter in the brain?

A
  • GABA: gamma-amino butyric acid
  • GABA occurs in brain tissues but not in other mammalian tissues at significant concentrations

• GABA functions as major inhibitory transmitter in many CNS pathways
– Functions throughout brain

• Transmitter at ~30% of all synapses in CNS

44
Q

How is GABA synthesised?

A

• GABA formed from glutamate by action of enzyme
– Glutamic acid decarboxylase (GAD)
– Enzyme found only in GABA-synthesizing neurons

(• GABA destroyed by GABA Transaminase within cells)

45
Q

What do you know about vigabatrin?

A

• Vigabatrin – synthetic analogue of GABA
– Inhibits GABA Transaminase by irreversible covalent binding
– Long lasting effect despite short plasma half-life

Increases GABA concentration in brain
– Increases GABA concentration in brain
– Effective in epileptic patients (resistant to other drugs)
– Generally well tolerated and relatively free from side effects

• Main drawback – depression and occasional psychotic episodes in minority of patients

46
Q

Ae drugs that increase GABA activity effective in treatment of abscence seizures?

A

– Absence seizures are paradoxically often exacerbated by drugs that enhance GABA activity

• Better treated by drugs acting by different mechanisms

47
Q

What does GABA transaminase convert GABA into and what can then happen to this?

A

Succinic semialdehyde

- can become succinate and enter TCA

48
Q

How is GABA concentrated in vesicles?

A

• Vesicular packaging via a transporter –

Like glutamate - transporter dependent on electrical potential across vesicle membrane

• Potential generated by ATP-dependent proton pump

49
Q

How is GABA taken up from the synapse and by what?

A

• Released GABA taken up by transporters

– Uses energy from Na+ gradient to drive uptake (co-transport)

– In pre-synaptic neurons : reutilized

– In post-synaptic neurons & glia

50
Q

What does Tiagabin do?

A

– inhibits GABA uptake and therefore increases GABA concentration

51
Q

What are the 2 main functional groups of GABA receptors?

A

• Ionotropic GABA receptors – post-synaptic
– Site of action of benzodiazepine drugs

• Metabotropic GABAB receptors – pre- & post-synaptic
– G protein coupled receptors

• GABA receptors identified in all regions of the brain

52
Q

How are GABA receptors structured?

A
  • Each receptor made up 5 subunits
  • Each subunits has 4 transmembrane spanning domains

Most likely composition is 2alpha 2Beta 1gamma

Most prevalent combination in  brain:
alpha1, beta2, gamma2 (60%)
Others:
alpha2, beta3, gamma2 (15-20%) 
alpha3, beta3, gamma2 (10%)

GABA binding sites (2) at interface of alpha & beta subunits

Benzodiazepine binding site at interface of alpha & gamma 2 subunits

Expression of each subtype varies in different brain regions (e.g. alpha6 expressed almost exclusively in b ll ) cerebellum)

53
Q

How do GABA receptors basically work?

A

• GABAA receptors are Cl- selective ion channels

– Reversal potential near 70mV

– Hyperpolarize neuron or ‘clamp’ voltage near resting potential

• Inhibit depolarization responses to excitatory inputs

54
Q

Name a GABA receptor agonist?

A

• Muscimol from hallucinogenic mushrooms

55
Q

2 GABA antagonists?

A

• bicuculline
- Convulsant alkaloid - inhibits GABAA receptors by binding to the GABA binding site

• picrotoxin
- Another convulsant - blocks the chloride channel

56
Q

Types of GABA modulators drugs?

A
  • Benzodiazepines
  • Barbiturates
  • Neurosteroids (e.g. pregnenelone, alphaxolone)
  • Ethanol
  • Anaesthetics
57
Q

How do benzodiazepines work?

A

Benzodiazepines – Selectively potentiate GABA effects on GABAA receptors
– Bind to an accessory site – not the GABA binding site

  • Located at a site of alpha subunit interaction with gamma subunit
  • Facilitates binding of GABA by allosteric action
  • Enhances effect of GABA Enhances effect of GABA

• Increase probability of channels opening
– no effect on channel conductance or open time

58
Q

What three GABA agonists of the benzodiazepine family do you know?
What are their relative durations of action?

A
  • Diazepam – long lasting as metabolized to active metabolite
  • Clonazepam – long lasting parent compound
  • Lorazepam, Temazepam – short lasting, no active metabolite
59
Q

What is a GABA antagonist, can act as a convulsant and can be used as an antidote to benzodiazepine overdoses?

A

• Flumazenil

– can act as a convulsant

• Used as antidote for benzodiazepine overdoses

60
Q

What are the clinical effects of benzodiazepines?

A

– Anxiolytic
• Used mainly for acute anxiety
• Use reducing in favour of antidepressant drugs and Cognitive Behavioural Therapy.

– Sedative
• Decrease time to sleep onset & increase time asleep
• Sleep effects tend to decline when drug taken for 1-2 weeks –

  • Reduction of muscle tone
    • Feature of anxiety in humans
    • Contributes to aches, pain and headache in anxious patients
    • Possible without appreciable loss of coordination

– Anticonvulsant
• Diazepam (i.v.used to treat status epilepticus)
– Acts rapidly compared to other drugs
• Clonazepam claimed to be relatively selective anti-convulsant
– Sedation a concern
– Withdrawal may exacerbate seizures

– Amnesia
• Reduced memory of events experienced while taking Benzodiazepines
• Minor surgery without unpleasant memories

61
Q

What are the side effects of benzodiazepines during use?

A

– Drowsiness

– Confusion

– Amnesia

– Impaired coordination

– High degree of tolerance and dependence

62
Q

What happens in acute toxicity from benzodiazepines?

A

– Overdose less dangerous than other anxiolytic/hypnotic drugs

– Prolonged sleep without depressing respiration/cardiovascular function

– With alcohol – respiratory depression

• Treated with antagonist, Flumazenil

63
Q

What are the withdrawal symptoms for benzodiazepines?

A

– Anxiety, increase in irritability and aggression

– Tremor and dizziness

64
Q

How might it be possible to separate the undesirable affects of benzodiazepines from the desirable effects?

A

• Action at alpha1 subunits leads to unwanted side effects (sedation) – Action at alpha2 and/or alpha3 containing receptors responsible for desirable anxiolytic effects without side effects

– Prospect that selective alpha2/3 acting ligands could be superior anxiolytic drugs

65
Q

What are barbiturates?

A

• Barbiturates discovered in the early 20th century

• Bind to GABA receptor at different site to benzodiazepines
– Potentiate GABA effect

  • Less specific receptor activity than Benzodiazepines
  • Widely used as sedatives until 1960s
66
Q

What can result from barbiturate overdose?

A
  • death from respiratory and cardiovascular depression
67
Q

Clinical effects of barbiturates?

A

– Sedative effects

  • impaired cognition
  • motor coordination
68
Q

Why are barbiturates rarely used?

A

– High degree of tolerance and dependence

– Strongly induce hepatic cytochrome P450 enzyme
• Enzymes that break down many drugs
• Drug drug interactions

69
Q

What three barbiturates do you know and when they are used, what is it for?

A

• Pentobarbital
- occasionally used for sleeping pills and anxiolytic but less safe than benzodiazepines

  • Phenobarbital – still used for anticonvulsant activity
  • Thiopental – used as an intravenous anaesthetic
70
Q

Where are neurosteroids made and when are their levels increased?

A
  • Neurosteroids (e.g. allopregnanolone)
  • Locally synthesized in CNS in glial cells from cholesterol or steroidal precursors

• Increased synthesis of endogenous neurosteroids in the brain during
– stress
- pregnancy
- after ethanol consumption

71
Q

How do neurosteroids affect GABA activity?

A

• Two binding sites on alpha sub-unit
– Potentiates
– Recent evidence that can also directly activate channel

• Enhance GABA-mediated chloride currents

72
Q

What synthetic neurosteroid do you know?

A

• - alphaxolone - developed as anaesthetic agents

– Veterinary usage

73
Q

Disrupted steroid regulation of GABAergic transmission is implicated in several debilitating conditions. What are these?

A
  • panic disorder
  • depression
  • schizophrenia
  • some forms of epilepsy
74
Q

How does ethanol affect GABA receptors?

A

– Multiple sites of action in CNS

– Acute GABA receptor potentiation similar to benzodiazepines

– Longer term modifications (receptor location, subunit composition, neurosteroids etc)

– Other sites include - Voltage gated Ca2+ channels

75
Q

Do anaesthetics work on GABA receptors?

A

– GABA receptors one site of action for some general anaesthetics

  • Etomidate
  • propofol
  • thiopental

– Act at different site to benzodiazepines

• Volatile anaesthetics (e.g. isoflurane, enflurane)

76
Q

He does GABA inhibit nervous transmission presynaptically?

A

– Inhibition of voltage-gated Ca2+ channels
- decrease transmitter release

– Occurs on glutamate, GABA and other transmitter containing pre-synaptic terminals

77
Q

He does GABA inhibit nervous transmission presynaptically?

A

– Increased opening of K+ channels

  • reduced firing of post-synaptic neurone
78
Q

Outline how glycine involved in the CNS as an NT

A

• A major inhibitory transmitter in vertebrate CNS

– Especially in spinal cord and brainstem

– Critical for regulation of motoneurons

Functions in:

  • retina
  • auditory system
  • sensory systems
79
Q

What is glycine made from and by what enzyme?

A
  • Serine

- Serine hydroxymethyl transferase

80
Q

How is glycine stored presynaptically and what takes it up from the synapse?

A

• Small pool of glycine packaged into synaptic vesicles
– H+-dependent vesicular inhibitory amino acid transporter (VIAAT)

• Released glycine taken up by transporters (GLYT1 & GLYT2)
– Astrocytes – terminates transmitter action
– Pre-synaptic neurons – replenishes pre-synaptic pool
– Driven by Na+ & Cl- gradients

81
Q

How are glycine receptors structured?

A
  • Like GABAA receptors – pentameric (5 subunits)
  • Four types of alpha subunits; one type of beta subunit known

• Composed of alpha (3) & beta
(2) subunits or alpha (2) & beta (3)

– Each 4 transmembrane spanning domains

82
Q

What compounds that affect the glycine receptors do you know?

A
  • Strychnine (antagonist)
  • glycine (agonist)

Both of above bind to alpha subunit

• Picrotoxin – non-competitive inhibitors at glycine receptor alpha subunit

83
Q

What specifically makes glycine receptors inhibitory?

A

• Ion channels permeable to Cl-

– Activation generates a hyperpolarizing ipsp

84
Q

What therapeutic drugs do you know that act on glycine receptors?

A

• No therapeutic drugs act specifically on glycine receptors

85
Q

Do you know a condition caused by a mutation in the glycine receptor?

A

Hyperekplexia

– Rare dominant mutation - single amino acid on alpha1 subunit

– Leads to 100-fold decrease in glycine affinity

– Greatly reduced glycine sensitivity

– Increased muscle tone, increased startle reflex

Neuroscience (16 decks)

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