CNS Flashcards
(51 cards)
1
Q
Describe the blood brain barrier and how it is different from a general capillary.
A
- the pore is blocked with transporters
- capillary is surrounded by the end feet of multiple astrocytes
2
Q
List the four AA CNS neurotransmitters, and whether they are inhibitory or excitatory.
A
GABA - inhibitory
Glycine - inhibitory (mainly)
Glutamate - excitatory
Aspartate - excitatory
3
Q
Which AA is starting molecule for other compounds?
A
glutamate
4
Q
Describe the lifecycle of Glu and Gln
A
- released glutamte (Glu ) is captured partly by neurons and partly by astrocytes (via excitatory AA transporter)
- astrocytes convert most of it to glutamine (Gln) via glutamine synthase -> gets out of astrocyte and into neuron by Gln transporters
- neuron can convert Gln into Glu with glutaminase
- Glu gets concentrated in vesicles, through the use of a pump (Glu transporter)
5
Q
How does glycine affect NMDA receptor glutamate responses?
A
- Gly is a positive allosteric modulator
- together Glu and Gly have a much greater response
6
Q
What would happen if glycine site on NMDA receptor was blocked?
A
-much less responsiveness
7
Q
How do PCP and ketamine affect NMDA receptors?
A
- binds to site within ion channel
- blocks ion movement down concentration gradient
- non-competitive antagonist (dif site to Glu)
8
Q
How does memantine affect NMDA receptors and how could it help Alz patients?
A
- non-competitive antagonist
- blocks ion channel
- can help protect the surviving neurons by reducing ion flow
9
Q
Describe the lifecycle of GABA
A
- GABA synthesised from glutamate by GAD
- GAT1 are reuptake transporters on presynaptic cell, and GAT2/3 on glial cells
- recycled GABA can be degraded by GABA-T to glutamine -> easy to transport
10
Q
How do benzodiazepines affect GABA A receptors?
What 3 other compound types have the same effect?
A
- positive allosteric modulators
- increase inward Cl- current
- barbituates, neurosteroids and alcohol
11
Q
What effect do GABA A receptors have generally?
A
- post-synaptic
- activation leads to hyperpolarisation due to inward movement of Cl-
- AP less likely
12
Q
How do GABA B receptors function generally?
A
- activation of heterodimer inhibits adenyl cyclase via G-proteins
- increase outward K+ and reduce inward Ca2+
- both effects reduce post and pre-synaptic excitability
13
Q
How does baclofen affect GABA B receptors and what condition can it treat?
A
- baclofen is a derivative of GABA and agonist of GABA B receptors
- can treat spasticity (involuntary tight/stiff muscles) as reinforces inhibitory input
14
Q
Which receptors does GHB affect and how?
A
GHB is an agonist of GABA A and partial agonist of GABA B
15
Q
How is glycine cleared from synapses?
A
- via transporters
- Gly T1 into astrocytes
- Gly T2 into presynaptic neurons
16
Q
What receptor does strychnine affect and how?
A
- competitive antagonist for glycine receptors
- blocking inhibitory means more excitatory response
17
Q
How does tetanus toxin effect the body and how?
A
- toxin migrates to CNS
- blocks glycine release from inhibitory interneurons
- means more reflex hyperactivity and muscle spasms
18
Q
What was HM’s accident, and what symptoms did he have?
A
- bicycle accident at age 9
- knocked out for 5 mins
- minor seizures until 16
- after this had multiple seizures and blackouts every week
19
Q
What surgery did HM have and what changed with his symptoms?
A
- bilateral medial temporal lobe resection (both medial temporal lobes goneskies)
- IQ improved and epilepsy cured
20
Q
What were the memory side effects from HM’s surgery?
A
- profound anterograde amnesia
- partial retrograde amnesia (up to 2 years prior)
- short-term memory was fine until his attention shifted
21
Q
Define the types of declarative/explicit long-term memory:
A
Declarative is things you know that you can tell others.
Episodic - events that occurred in relation to time context
Semantic - historic/facts
22
Q
Define the types of procedural/non-declarative long term memory:
A
Skill-learning: riding a bike
Priming: more likely to use a word you heard recently
Conditioning: salivating when you see a steak
23
Q
What did HM teach us about memory?
A
- medial temporal lobs are critical for forming types of long-term memories
- many dif kinds of memory
- forming/consolidating new episodic memories is dependent on the hippocampus -> in the medial temporal lobe
24
Q
What is happening in the synapses to allow long term potentiate (LTP)?
A
- increased Glu release allows more Na to enter with greater depolarisation
- forces Mg out of NMDA pore
- subsequent Ca flow activates protein kinases
- protein kinase 1/CAMKII makes AMPA more sensitive to Glu
- protein kinase 2 (via NO) triggers more Glu release
- also get metabotrophic receptors, enzymatic and other long term changes
25
How does CAMKII enzyme help LTP?
- phosphorylates AMPA receptor
- makes them more permeable to Na
- increases resting potential of the cell making it more sensitive to incoming impulses
- more AMPA receptors at synapse
26
What is the extracellular amyloid plaque hypothesis for AD?
- APP protein is broken down by series of secretases
- AB42 forms when gamma secretase cuts 2 AA too long
- insoluble fragments called AB42 accumulates outside cell
- sticky AB42 forms amyloid plaques
27
Describe how intracellular neurofibrillary tangles may contribute to AD?
- microtubules are railropad tracks
- tau proteins tie together and stabilise the microtubules
- in AD tau proteins get tangled and cluster
- structure unstable
- loss of axonal transport results in cell death ACh
28
What is the most severely affected neuron type in AD and what drug can help?
-ACh neurons
-normally AChE breaks down ACh into choline and acetate in the synapse, as ACh has a short duration of action
-inhibiting AChE will increase the action of ACh in synpases
-Drug examples: donepezil, rivastigamine and galantamine
(done at the river, gal)
29
How can memantine help with AD?
- blocks NMDA receptor ion channel
- noncompetitive NMDA receptor antagonist
- at high conc can inhibit learning and memory
- at low conc, can promote synaptic plasticity and preserve neurons -> slows entry of Ca into cells
- minor cognitive function improvements
30
What areas in the brain are mainly affected with AD?
-focus on language and memory (temporal lobes and hippocampi)
31
What is LATE and how does it differ from AD?
- another form of dementia
- mimics symptoms of AD
- similar symptoms but progresses more slowly
- different protein build up -> TDP43
32
What is aducanumab and how does it work?
-first drug to target amyloid plaques
| monoclonal antibody treatment may prevent plaque formation or remove B-amyloid from brain
33
What could sound waves and microbubbles do for AD?
-non-invasive ultrasound tech that may clear the brain of amyloid plaque and restore memory function
34
What are the main features of vascular dementia?
- associated with vascular risk factors
- can co-exist with other dementias
- depends on severity of vessel damage and the brain region affected-> but mostly frontal cortex
35
How is vascular dementia treated?
- some AD meds may help
| - proactive CVD health factors may slow damage
36
What is lewy body dementia (LBD)?
- incl parkinsons and dementia with lewy bodies
| - earliest symptoms differ but same changes in brain
37
How is LBD different from AD?
- LBD varies from day to day in severity of memory issues
- LBD is build up of LB proteins in brain
- LBD has flat facial expressions/no facial muscle control
- potential for REM sleep behaviour disorder
- AD doesnt have physical symptoms until quite late
38
How is LBD treated?
- AchE inhibitors may help improve alertness and reduce hallucinations
- if moderate or severe memantine may help
- carbidopa-levodopa reduces parkinsonian signs
39
What does parkinsons have that LBD doesn’t and what are the consequences?
- diminished pigment/neuron loss in the substantia niagra
- origin of dopaminergic innervation of the striatum
- regulates posture and muscle tone
40
How does L-dopa therapy work for parkinsons and what other drug goes with it?
- L-dopa is main drug bc dopamine cannot cross BBB, but l-dopa can
- dopaminergic receptors in brain then convert it to dopamine
- carbidopa is an enzyme inhibitor that prevents the conversion of L-dopa to dopamine before the drug reaches the brain
- helps 10% L-dopa reach brain rather than just 1-3 % of L-dopa alone
41
What is frontotemporal dementia/picks disease and its key features?
- FTD affects higher order functions
- loss of cells in frontal and temporal lobes of brain
- key feature is behavioural
- impulsive behaviours and disinhibition
- change in personality
42
What causes FTD/picks disease?
- abnormal clumps of tau proteins called pick bodies
- they derail transport system of microtubules in brain
- same misfolded protein as in AD, but very different "wrong" fold
43
What treatment is used for FTD?
- SSRIs increase seratonin
| - anti-psychotics may help behaviour; increase noradrenaline and serotonin
44
Describe cell necrosis pathway
- injury/disease pathology
- cells swell
- chromatin is digested/hydrolysed
- cytoplasm and organelle membranes disrupted
- entire cell lyses
- inflammation/immune activation occurs
45
How does calcium contribute to necrosis?
- calpains are proteolytic (cut proteins) and are regulated by Ca conc.
- calpains activate caspases (cleave proteins)
- calpains activate the rupture of lysosomes and cathepsin (another protease) escapes
46
What is apoptosis?
- programmed cell death
- cell shrinks
- bubble like blebs on surface
- break into small bubble-wrapped fragments
- phagocytic cells engulf fragments and also secrete anti-inflammtory cytokines
47
How does excitotoxicity lead to cell death and what are the consequences?
- Glu binds to its receptors
- triggers influx of Na and Ca ions along with water into presynaptic neuron
- neurons swell and die
- these neurons then release Glu and cycle continues
- can play central role in ischemic stroke brain damage (downstream of blood clots)
- starving neurons release excessive Glu
48
How do telomeres contribute to aging and how can we protect them?
- they are caps on end of chromosomes and protect DNA
- when the caps disappear overtime as cells divide, cells age as DNA no longer protected
- standard nutrition things - AOX, oily fish etc
- physical exercise stabilises telomeres
49
What vitamin can slow progress of some of AD?
-vitamin E can maybe prevent or delay mild cognitive impairment
50
What are the receptors for glutamate?
- NMDA
- Non NMDA
- mGlut
51
What is meant by a positive allosteric modulator?
When one is present, it enables that receptor to respond to a greater extent
