Synapse Formation

Question 1

What are muscles innervated by?

Answer 1

Motor neurons

Question 2

What are the 3 cells involved in neuromuscular junction synapses?

Answer 2

• Axon terminals
• Muscle fibres
• Schwann cells

Question 3

Where do synapses happen in the muscle?

Answer 3

• Synapses made at shallow depression in muscle
  
  • Sarcolemma invaginated at syapse to form deep, regular post functional folds

Question 4

What is a post junctional fold?

Answer 4

Present at the troughs and crests:

• at crest: loads of ACh receptors
• at troughs: lots of voltage gated Na⁺ channels

Question 5

Outline the basic process of the neuromuscular synapse.

Answer 5

• single transmitter ACh released froma axon
• single NT type - nicotinic AChR expressed on post synaptic membrane
• motor neuron forms a bouton above synapse, surrounded by schawnn cell, bouton contains large number of synaptic vesicles and synaptic vesicle dockery and fusion proteins

Question 6

Where is ACh receptor expressed?

Answer 6

On surface of muscle cell

Question 7

How are AChR pre-patterened to the centre of muscle fibres before motor axons arrive?

Answer 7

AChR clusters are stabilised at synaptic sites whilst extra AChR is lost. Muscle secretes neurotrophic factors to promote for survival of innervating motor axons

Question 8

How are short opening periods of the AChR achieved after motor axon innervation?

Answer 8

• AChR made of 4 subunits: α, γ, β, δ - characterised when receptor bind to receptor and ion pore
• After motor neuron axon is innervated, muscle fibre gets change in composition of AChR, get v short opening periods allow high level of current to flow through

Question 9

How is expression of post-synaptic AChRs induced? (8 marks)

Answer 9

1. Innervating motor axons secrete proteoglycan Agrin - this binds to Lrp4
2. Agrin/Lrp4 form complex with dimers of TRK Musk - each Musk molecule is phosphorylated at tyrosine residue Y553
3. Y553 phosphorylation recruits Dok7 adapter protein leading to its dimerization and phosphorylation
4. Dok7 dimeriation and phos, increases Musk activity and recruits Crk/ Crk-L
5. JNK and Rho/ Rac GTPase activation results in Rapsyn binding to AChR cluters and their stabilization

Question 10

What do motor axons do at a potential synapse?

What does this suggest about Agrin and Musk signalling?

(4 marks)

Answer 10

• Don’t stop growing and develop synaptic boutons at presumptive synapse
  
  • They express AChR
• Suggests agrina nd musk signalling generates a muscle derived trophic molecule required for synaptic bouton formation and maturation

Question 11

What have transgenic mice revelead the importance of Musk, Lrp4 and Dok7?

Answer 11

That they are all essential for expression of central motor neuron AChR clusters before innervation

Question 12

Where is the only place that synapses can be made in the CNS?

Answer 12

Dendritic shaft - as they can be both inhibtory as well as excitatory

Question 13

Name a few of the pre-synaptic proteins in the pre-synaptic zone. (4 marks)

Answer 13

Synaptic vesicle

Fusion proteins

Synaptic vesicle docking proteins

Scaffolding proteins

Question 14

Why are post synaptic membranes electron dense?

Answer 14

High level of neurotransmitter receptors expressed and scaffolding proteins

Question 15

What do scaffolding proteins do in the pre-synaptic zone?

Answer 15

Form structure for docking fusiom proein to bind to e.g. Piccolo (scaffolding protein)

Question 16

What do excitatory glutamatergic synpases contain?

Answer 16

Scaffolding proteins e.g. PASD-95, and cluster NMDA and AMPA receptors and their associative signalling molecules

Question 17

What kind of molecules are in teh excitatory post-synaptic density?

Answer 17

• Post synaptic adhesion proteins e.g. cadherins
• Ion channels e.g. AMPA and NMDA glutamate receptors
• Scaffolding proteins e.g. PSD-95
• Signalling molecules e.g. CamKII

Question 18

What are the first stages in excitatory synapse development?

Answer 18

1. Incoming growth cone releases neurotransmitter
2. If dendrite expressed is suitable, NTRs is attracted to the axons
3. Interaction between pre and post synaptic adhesion proteins stabilises the developing synapse and initiates synaptic maturation

Question 19

What is the second stage in excitatory synapse development?

Answer 19

1. Prefabricated components of presynaptic active zone are transported to the zone in pre-assembled transport vesicles
2. Vesicles deposit pre-synaptic components inot the actie zone
3. Lots of transport vesicles associated with scaffold proteins Bassoon and Piccolo which engage with microtubule motor protein dynein

Question 20

What is the 3rd stage in excitatory synapse developement?

Answer 20

1. Scaffolding proteins recrutied to intracellular domains of post synaptic adhesion proteins
2. NMDA receptors inserted into post-synaptic membrane (synapses at this point non-functional even though NMDA receptors present they are gated and therefore need AMPA receptors)
3. Post syn mem, lacks AMPA receptors so immature synapses silent
4. So, insertion of AMPA receptors into post syn membrane (modulated by Pentraxins) produce functional synapses

Question 21

List some differences between excitatory and inhibtory synapses.

Answer 21

Question 22

Name some synaptic adhesion proteins - pre and post synaptic partners

Answer 22

Question 23

What do the 3 proto-cadherin clusters contain?

Answer 23

Question 24

What sort of tetramers are protocadherins functional as?

Answer 24

Homo and hetero tetramers

Question 25

What are protocadherins function? (2 marks)

Answer 25

To act as molecular bar codes to identify and distinguish different neuronal types. Synapses won’t fomr when the molecular bar code of hte to neurons are too similar

Question 26

As development proceeds what are synaptic connections primarily defined by?

Answer 26

Synaptic eliminations