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Disease in the brain > Cholinergic signalling (done) > Flashcards

Cholinergic signalling (done) Flashcards

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1
Q

Which NS is ACh found in?

A

Both PNS & CNS

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2
Q

What are the main roles of ACh?

A
  • Major function in movement (muscle contraction in PNS, motor control in CNS)
  • Roles in attention, learning & memory
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3
Q

What does ACh do at the NMJ?

A

ACh mediates direct control of skeletal muscle tension at NMJ

(Modulation of timing & tension in the cardiac & smooth muscle mediated by ACh released by postganglionic parasympathetic neurons

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4
Q

What are the 2 classes of cholinergic receptors?

A
  • Nicotinic (nAChR)
  • Muscarinic (mAChR)
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5
Q

Who discovered ACh & how?

A

Otto Loewi (1921)

Used 2 frog hearts & stimulated the vagus nerve - HR slowed down, he realised vagus nerve must be releasing signals onto heart

Found vagus nerve was supplying chemical substances to organs = ACh

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6
Q

Who were the 2 guys involved in discovering ACh?

A

Henry Dale & Otto Loewi

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7
Q

How many clusters of cholinergic projections are there?

A

8 clusters

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8
Q

What are cholinergic projection neuron clusters (Ch)1-4 called?

A

Medial Septal Group

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9
Q

What is the Medial Septal Group?

A

Ch1-4 in the basal forebrain target cortical & limbic structures (attention, learning, memory)

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10
Q

What are cholinergic projection neuron clusters (Ch)5-6 called?

A

Pontine Cholinergic System

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11
Q

What is the Pontine Cholinergic System?

A

Ch5-6 in the caudal midbrain target the thalamus, midbrain & cerebellum (sleep, arousal & motor function)

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12
Q

What are Ch7-8 cholinergic projections?

A

In the midbrain target the brainstem & midbrain (motor/sensory function)

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13
Q

What are the 2 sets of neurons in the PNS?

A
  • Preganglionic neurons
  • Postganglionic/postsynaptic neurons
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14
Q

What are preganglionic neurons?

A
  • Cell bodies in the brain & spinal cord (CNS)
  • Synapses on neurons in an autonomic ganglion located near or in effector organs
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15
Q

What are postganglionic/postsynaptic neurons?

A
  • Cell bodies in the ganglion
  • Synapses on the effector
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16
Q

What is a ganglion?

A

Collection of PNS neuron cell bodies

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17
Q

What can the neurons in the PNS do depending on receptors?

A

Can stimulate or inhibit muscle contrations depending on receptors

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18
Q

What is ACh synthesis catalysed by?

A

By the enzyme choline acetyltransferase (ChAT)

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19
Q

What does ChAT (choline acetlytransferase) do to make ACh?

A

Transfers the acetyle group (CH3CO-) from acetyl-Coenzyme A (Acetyl-CoA) to choline

Forming ACh

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20
Q

What is ACh synthesised from?

A

From dietary precursors

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21
Q

What are the dietary precursors that make choline?

A
  • Egg yolks
  • Liver
  • Fish
  • Grains
  • Nuts
  • Soya
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22
Q

What are the dietary precursors that make acetyl-CoA?

A

From breakdown fo glucose

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23
Q

What are the 6 stages of synaptic ACh synthesis, release & recycling? (Short version)

A

1 - Synthesis
2 - Storage
3 - Release
4 - Effect
5 - Recycling
6 - Reuptake

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24
Q

What are the 6 stages of synaptic ACh synthesis, release & recycling? (Long version)

A

1 - Synthesis = Cytosolic choline acetlytransferase (ChAT) synthesis ACh

2 - Storage = Vesicular ChT loads ~10,000 ACh molecules into each 40-50nm vesicle

3 - Release = Action potential causes Ca2+ –> mediated vesicular release (~300 vesicles/AP)

4 - Effect = ACh diffuses across the synapse & activates post-synatic recpetors (EPSP, ~2ms)

5 - Recycling = ACh is metabolised to choline + acetate by acetylcholine esterase (AChE)

6 - Reuptake = ~80% of choline is taken up by presynaptic cell for resynthesis (Na+ dependent channel)

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25
What is a motor unit at the NMJ?
Single motor neurone & all muscle fibres innervated (Each motor unit functions as an individual unit)
26
What is focal innervation?
1 synapse per muscle fibre = innervation from 1 motor unit only
27
What is the safety factor at the NMJ?
8-10x the amount of ACh required is released This means = 100% sucess rate of muscle contraction when a motorneurone fires
28
Where does muscle innervation come from in the SC?
The anterior ventral horn
29
What is the process of a signal reaching the NMJ?
--> Cell bodies in anterior ventral horn of SC --> Signal goes to motor neurons (Alpha motor neurons) --> Goes to innervate musce fibres at the NMJ --> by activating Nicotinic receptors on muscle fibre
30
Refer to slide 3.4 for diagram of NMJ
:)
31
What are the 3 stags of ACh recycling & resynthesis?
1 - Degredation 2 - Reuptake 3 - Resynthesis
32
What happens in the Degredation (1) stage of ACh recycling & resynthesis?
- ACh can't be transported back into the neuron - It is broken down in the synaptic cleft by the enzyme AChE in microseconds into: ACh = choline + acetate
33
What happens in the Reuptake (2) stage of ACh recycling & resynthesis?
- Choline taken back up into presynaptic cholinergic nerve terminal by energy dependent co-transport system w Na+ - Choline reuptake is the RATE LIMITING STEP in ACh synthesis
34
What happens in the Resynthesis (3) stage of ACh recycling & resynthesis?
Choline acetyltransferase (AhT) in neuronal cytosol combines choline w acetyl coenzyme A (to mkae ACh) Acetyle CoA = derived from mitochondria & Krebs cycle
35
Bit of interesting context & might help u remember - he said this won't be on the exam: Nerve gas & the NMJ:
VX & sarin nerve gas are organophosphates (like pesticides): - Potent AChE inhibitors - Prevent degredation of ACh --> builds up in motor end plate preventing muscle relaxation - Rapidly leads to death via muscle paralysis & asphyxiation
36
What are the 2 types of ACh recpetors?
Nicotinic & Muscarinic receptors
37
What type of channel are Nicotinic recptors & how do they work?
Ionotropic/ion channels They directly activate neurons by changing ion concentrations
38
Which type of ACh receptor is an ionotropic channel?
Nicotinic receptors
39
What type of channel are muscarinic recpetors & how do they work?
Metabotropic/G protein-coupled receptors They use intracellular 2nd messengers
40
Which type of ACh receptor is a metabotropic/G protein couped receptor?
Muscarinic receptors
41
What are the characteristic of Nicotinic receptors? (4 points)
- Pentameric channel (5 subunits) - 11 subtypes - Major recpetors at NMJ - Also found in neurons
42
What are the characteristics of Muscarinic receptors? (2 points)
- 5 subtypes (M1-M5) - Can be excitatory (M1, 3, 5) or inhibatory (M2, 4)
43
Are nicotinic receptors excitatory or inhibatory?
They are ALL excitatory
44
What do nicotinic receptors mediate?
They mediate fast neurotransmission in PNS & excitation/neuromoduclaiton in CNS
45
What is the structure of Nicotinic recptors like?
- They are Pentameters --> which contain at least 2 alpha subunits - Each a subunit binds one molecule of ACh
46
Why are the 2 alpha subunits in Nicotinic receptors so important?
Subunit composition affects: - Ion selctivity - Agonist affinity - Localisation - Kinetics - Desnsitisation
47
What are the 2 subdivisions of Nicotinic receptors?
- Muscle-type receptors at te NMJ (N1 or Nm) - Neuronal subtypes (N2 or Nn)
48
What are the 2 divisions of muscle-type Nicotinic receptors at the NMJ? (N1 or Nm)
- Embryonic form (α1, β1, γ, and δ subunits) - Adult form (α1, β1, δ, and ε subunits – higher conductance, shorter opening time)
49
What are the neuronal subtypes of Nicotinic recrptors like?
They are a combination of twelve different nicotinic receptor subunits: α2−α10 and β2−β4.  --> Homomeric (one type of subunit) --> Heteromeric (at least one α and one β subunits)
50
Where are the 5 subtypes of Muscarinic AChRs found?
- All found in CNS - M1-M4 also found in other tissues
51
What family of receptors are muscarinic receptors in?
Part of a large family of G-protein coupled receptors (They use an intracellular secondary messenger system --> to transmit signals inside cells)
52
Which of the subtypes of muscarinic AChRs are excitatory vs inhibitory & what are they coupled with?
Excitatory --> M1, M3 & M5 (Gq coupled) Inhibitory --> M2 & M4 (Gi coupled)
53
Where are each of the excitatory muscarinic AChRs found?
M1 = enteric & neuronal M3 = glandular & vascular M5 = CNS
54
Where are each of the inhibitory muscarinic AChRs found?
M2 = cardiac M4 = CNS
55
What are the actions of the excitatory muscarinic AChRs (M1, M3, M5)?
- CNS excitation - Gastric acid secretion - Gastrointestinal motility - Glandular secretion - Contraction of visceral smooth muscle - Vasodilation
56
What are the actions of inhibitory muscarinic AChRs (M2, M4)?
- Cardiac inhibition - Presynaptic inhibition - Neuronal inhibition
57
What is the cascade(?) action that happens when an agonist acts on an excitatory muscarinic AChR? (Need to go back thru video to clarify this - just assuming from the slide lol)
- ↑ IP3, DAG - ↑ Intracellular Ca2+ (Stimulation) - ↓ K+ conductance (Depolarisation)
58
What is the cascade(?) action that happens when an agonist acts on an inhibitory muscarinic AChR? (Need to go back thru video to clarify this - just assuming from the slide lol)
- ↓ cAMP - ↓ Ca2+ channel (inhibition) - -K+ conductance (slow IPSP)
59
Pls look at slide 4.4 for good diagram of division of cholinergic receptors
mmmmm
60
Where are nicotinic & muscarinic both highly expressed?
In the cortex & hippocampus Play a neuromodulatory role increasing (nicotinic) or decreasing (muscarinic) synaptic release probability
61
Which muscarinic receptors are found in the following brain areas?
SN/VTA = mostly M5 Hippocampus = M1-M4 Cortex = mostly M1, M2, M4 (M2>M4) Striatum = mostly M1, M4, M2 (M4>M2) Cerebellum = mostly M2, M1 (M3>M4>M5)
62
What can manipulation of ACh levels do to the brain?
It affects a range of cognitive functions --> particularly attention, learning & memory ACh depletion also contributes to normal age-related cognitive decline
63
What are the 3 types of drugs that are used to manipulate cholinergic transmission?
- AChR agonists - Acetylcholinesterase (AChE) inhibitors - AChR antagonists
64
What do AChR agonists do (the drug)?
- Mimic the effects of ACh on AChRs - Nicotine & muscarinic receptors - Improve cognitive function
65
What do Acetylcholinesterase (AChE) inhibitors do (the drug)?
- Prevent ACh degredation & inc ACh levels at synapses - Improve cognitive function in AZs disease (e.g. Donzepil) --> irreversible inhibitors are toxic!!!
66
What do AChR antagonists do?
- Block the effects of ACh at receptors - Produce memory impairments as in AZs disease (e.g. scopolamine & atropine)
67
What do AChR antagonist drugs do?
- Block the effects of ACh at receptors - Produce memory impairments in AZs disease (e.g. scopolamine & atropine)
68
What was the test used to prove that vigilance is controlled by ACh?
Vigilance tasks req sustained attention Task: detecting rare & unpredictable target stimuli - Letter or digits presented in random order - Subject must respond to specified targets Measures: - Response time to target - Omission & false alarms
69
What did the study on ACh & vigilance show about scopolamine?
IMPAIRS vigilance task performance == slower responses, more errors
69
What did the study on ACh & vigilance show about nicotine?
IMPROVES vigilance task performance == faster responses, less errors
70
What does scopolamine induce?
"Transient memory impairments" -> it is used as a model of cognitive deterioration (Scopolamine mimics age-related memory deficits)
71
How has scopolamine helped developing drug treatments?
Cholinergic drugs to treat AZs disease (e.g. AChE inhibitors) are evaluated on their ability to reverse scopolamine-induced memory impairments
72
How is cholinergic signalling involved in SZ?
- Smoking unusually prevalent in Schizophrenics - Mutations in the nicotinic a7 receptor inc the chance of developing SZ
73
How is cholinergic signalling involved in Parkinson's?
Dopaminergic activity is heavily regulated by both muscarinic & nicotinic receptor activity
74
How is cholinergic signalling involved in epilepsy?
Mutations in nicotinic receptors associated w Autosomal Dominant Nocturnal Frontal Lobe Epilepsy
75
How is cholinergic signalling involved in addiction?
- Nicotine activates mesolimbic DA pathways, resulting in addiction - Deleting M5Rs (DAerigic neurones) reduces reinforcement & withdrawal related behaviours
76
How is cholinergic signalling involved in Alzheimer's disease?
- Many neurologic & psychiatric impairments seen in AD are linked to disruption of the Cholinergic system - AChE-inhibitors are one of the ONLY available treatment options
76
Summary slide for a bit of reading:
- Cholinergic neurones deliver ACH throughout the PNS&CNS - effector molecule at NMJs, mediates autonomic NS actions in the periphery, roles in attention, cognition & motor control in the brain - ACh acts at inotropic nicotinic & metabotropic muscarinic receptors - Nicotinic receptors show functional diversity according to the subunit composition - Muscarinic receptors can be excitatory M1-type (M1/3/5) coupled to Gq/11 or inhibitory M2 type (M2/4) coupled to Gi/0 - ACh receptors are abundant throughout the brain, however there are significant differences in expression profiles between subtypes - Abnormalities in the cholinergic system have been linked to many disease states incl AZs

Disease in the brain (22 decks)

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