SYNAPSES

Question 1

What are the morphological changes that happen when a growth cone tuns into a pre-synapse?

Answer 1

1. Filopodia retraction
2. Membrane and extracellular glycoproteins added
3. Presynaptic vesicles, dense ECM, PSD, receptors accumulate in the cleft.

Question 2

What are some differences between pre-synapse and adult synapse?

Answer 2

1. Few and only small vesicles present
2. Narrow cleft between cells
3. Markedly thicker post synaptic density in the adult

Question 3

Although contacts made by the growth cone can and do initiate synapse, other parts of both the pre and post synaptic cell can also do this such as…………….

Answer 3

Axon branches

Dendritic filopodia

Question 4

In some neurons, pre-established presynaptic specialisations mark the future synapse and others are inhibited. In other situations random contacts form transient adhesions which, if stable, recruit other synaptic components pre and post synaptically and go onto form what>

Answer 4

Mature functional synapses also.

Question 5

When does synaptogenesis happen?

Answer 5

Mainly as axons reach targets but this varies greatly from region to region. Spinal cord, brain stem and other regions become functional pre-birth whereas most cortical synapses are created after birth.

Question 6

What can pre-synaptic specialisation can be induced or inhibited by what?

Answer 6

By non neuronal factors such as guidepost cells (that guide axons to targets)
These cells are often glia.

Question 7

Give an example of a glial secreted factor that guides axons and dictates presynaptic specialisation.

Answer 7

In C Elegans, RIA axons that from the pharangeal nerve ring are synpased upon by AIY interneurons but only at a specific point. Sheath cells locally secrete netrin which guides RIA axons ventrally. Netrin also causes its receptor to cluster in the AIY neurons which promotes the assembly of pre-synaptic terminals where their axons are adjacent to the glia. Loss of netrin leads to spreading of DCC and failure of the synapses to be localised.
Essentially, synapse sites can be dictated by axon guidance factors secreted from adjacent cells.

Question 8

What is synpase specification?

Answer 8

The selection of an appropriate contact.

Question 9

What is synapse induction?

Answer 9

The clustering of synapstic machinery.

Question 10

What are the best studied synapse-specific cell adhesion molecules?

Answer 10

Neurexins and neuroligins.

Question 11

What are the functions of neurexins and neuroligins?

Answer 11

They have large IC domains that can assemble intracellular components into the active zone and the post synaptic density.
They connect pre- and postsynaptic neurons at synapses, mediate trans-synaptic signalling, and shape neural network properties by specifying synaptic functions

Question 12

What is aberrant neuroligin-neurexin signalling strongly associated with?

Answer 12

Autism spectrum disorders

Shizophrenia

Question 13

What do neuroligins and neurexins allow?

Answer 13

Allows spatial segregation of different inputs/outputs. By differential expression of multiple members of the neurologin and neurexin families, different pre-synaptic neurons to select between different post synaptic partners. Different localisation of these molecules also allows separated innervation by excitatory and inhibitory pre-synaptic neurons. This can also allow multiple different inputs onto one post -synaptic cell.

Question 14

Multiple neurons get multiple inputs such as purkinje cells and parallel and climbing fibres in a spatially restricted manner. These synapses can be rearranged over time. What does this show about synapses.

Answer 14

They are plastic.

Question 15

What are the models of synapse formation?

Answer 15

1. Dendritic spines develop largely independently of the pre-synaptic inputs and dictate where these will be.
2. Pre-synaptic inputs induce spine formation.
3. Dendritic filopodia induce synapses in axons that are growing past (en-passant)

Question 16

Which of the models of synpase formation is true?

Answer 16

All of them seem to operate.

Question 17

Which models of synpase formation operate where?

Answer 17

Purkinje cells in the cerebellum produce dendritic spines even when their presynaptic partners are missing.
The main method of operating forebrain seems to be en passant synapse formation.

Question 18

In all cases, what does contacts between dendrite and axon trigger?

Answer 18

Calcium flux

Question 19

Contact between dendrite and axon may be mediated by what?

Answer 19

Directly through neurexins and neuroligins.
Through soluble factors released by pre or post synaptic cells such as Wnts.
These promote recruitment of scaffolding proteins that provide a framework for the formation of protein complexes that form the active zone and post synaptic density.

Question 20

What are CASK and PSD-95 examples of?

Answer 20

MAGUKs

These are scaffolding proteins that form the active zone and post synaptic density?

Question 21

Why is the neuromuscular junction easy to study?

Answer 21

It is accessible
It is a simpler synapse
It is a lot larger that other synapses

Question 22

What happens before innervation of a NMJ?

Answer 22

AChRs are present at low density and innervation leads to progressive clustering of not only AChRs but other channels such as GABA and glycine under the nerve terminal. Eventually, AChRs are only found beneath terminals in a high density.

Question 23

Spontaneous pre-clustering of AChRs pre innervation myotubes suggest the post synaptic cell may direct innervation. However, motor neuron neurites contact myotubes at random and new AChR clusters are born at these sites. The induced clustering is activity independent. What does this suggest?

Answer 23

Suggests the motor neuron secretes a factor that does the induction.

Question 24

How was it shown that it is the motor neuron that secretes a factor that induces clustering and not the post synaptic cell?

Answer 24

Biochemical purification from the electric organ of the Torpedo Ray identified a secreted ECM protein made by motor neurons that induces cluster on cultered myotubes.
This factor is Agrin.

Question 25

Motor neurons lacking agrin cause what?

Answer 25

Disrupted neuromuscular junctions and post synatpic differentiation with no clustering.

Question 26

What are the stages of receptor clustering?

Answer 26

1. AChR mRNA is expressed at low levels in the myotube nuclei and AChR channels are widely distributed at low density.
2. Agrin released by motor neurons binds to the Muscle Specific Kinase (MuSK) complex which autophosphorylates and recruits Rapsyn, which recruits and clusters AChRs.
3. Other factors release by the synpasing motor neuron growth cone (such as neuregulin) induce AChR expression in the synaptic nuclei nearby.
4. Ach is also release, and can bind to activate AChRs both in and away from the nerve terminal.
5. When this activity is not accompanied by agrin signalling, it inhibits AChR expressing in non-synaptic nuclei, and destabilises extra-synaptic AChR clusters.
6. The net effect is that AChRs are densely concentrated in the synapse but are scarce elsewhere.

Question 27

What plays a role in synapse stabilisation?

Answer 27

Activity

Question 28

What is the result of an ACh KO?

Answer 28

AChr clusters grow faster and larger.

Question 29

What is the results of MuSK KO?

Answer 29

No AchR pre-clusters nor immature or mature neuromuscular junctions.