Synaptogenesis Flashcards
How are the amount of synapses in the body altered throughout time?
Initially, many form, which are refined back in the adult
What happens when the growth cone contacts the post-synaptic target cell?
- Nerve cell differentiates
- Changes in the cell membrane on BOTH cells at the point of contact
- Specialised structures form in the membrane to allow chemical signalling to occur
Do all neurons form synapses in development?
No
What determines if a synapse survives or dies back?
Activity-based reinforcement
What are plastic changes of synapses involved in?
Learning and memory
Are there differences between synapses formed in development and in regeneration?
Some differences and some similarities
What must be present in order to form functional synapses?
- Correct receptors, which match the target tissue
- Synapses at the correct location
- Correct part of the membrane differentiating into a synapse
- Correct number of synapses made
(Work in the correct way and in the right place, between the right neurons)
What is dependant development?
Some cell types are dependant on being innervated (synapse formation) in order to differentiate
Which cells are contact dependant?
Muscle spindles
Which cells are contact independant?
Merkel cells (touch cells)
What are the morphological features of synaptic specialization between an auditory endbulb and a target: Spherical Bushy Cell?
- Small vesicles at the presynaptic membrane
- Narrow cleft (filled with ECM) between pre and post synaptic membranes
- Thickening of the postsynaptic membrane (post synaptic density)
- ECM matrix proteins accumulate, receptor recruitment, tight junction formation (in POSTSYNAPTIC membrane)
When does synaptogenesis occur?
When axons reach their targets, which is highly variable
In cats, why does synaptic density increase at post-natal day 10?
Cat opens eyes and this drives synapse formation in the retina (need sensory inputs)
When does synaptic density increase in the mouse?
Post-natal week 1
What dictates synaptic sites?
- Approaching growth cone communicates to the target by releasing a signal (eg. Ach when approaching a muscle target)
- May have pre-prepared sites on the post-synaptic membrane which contain adhesion molecules
How can site availability for a synapse be restricted?
Astrocytes may cover parts of the neuron (eg. cover the cell body so that only the dendrites are free for synapse formation)
What happens to adhesion when a growth cone CONTACTS its target?
Adhesion increases between the growth cone and the post-synaptic membrane
What is the structure of adhesion molecules?
Many different adhesion molecules
Many different domains
Many contain IMMUNOGLOBULIN domain
What happens to adhesion when a synapse matures?
Adhesion molecules become localised next to the synapse
What is the receptor in a neuromuscular junction and what does it bind?
Nicotinic AchR
Binds ACh
When a neuromuscular junction is formed, what are the early effects?
1) RECEPTOR CLUSTERING:
- Diffuse distribution of receptors in the membrane become a focussed distribution
2) INCREASE TRANSCRIPTION IN CELLS RECEIVING INNERVATION:
- Increase transcription in adjacent nuclei
- Decrease transcription in nuclei further away
What receptors cluster in developing myotubes?
AchR
What receptors are inhibitory?
Glycine and GABA
What receptors are stimulatory?
Glutamate
What does glycine use to cluster receptors together?
Protein called Gephyrin, which is bound to the receptors
Which receptor undergoes some clustering, before the neuron arrives?
AchR
Which axons induce receptor clustering
Motor axons
What induces receptor synthesis?
How?
ARIA (Ach receptor-inducing activity)
Increases AchR subunit mRNA (esp. e subunit, which replaces gamma subunit in a mature receptor)
Where is ARIA released from?
Motor neurons
What family is ARIA a part of?
Neuregulin family
Where are neuregulins found?
In the developing brain (CNS)
What do neuregulins do? (2 things)
Help to pattern synaptogenesis (get the right synapses in the right places, with the right strength)
Increase NMDA receptors in the developing cerebellum
How are many different neuregulins used in synaptogenesis?
To fine tune the process
How is the basal lamina important in synaptogenesis? (experiment)
- Coded roadmap which can be used in regeneration
- Helps to evoke clustering of receptors
Experiment:
- Denervated and destroyed muscle can grow back and reinvoke the formation of NMJs and receptor clustering
(ECM must help to do this as the only structure left)
Where is Agrin purified from?
T.californica AChR clusters
Where is Agrin made?
In BOTH motorneurons and muscle
What can be used to study why AchRs cluster?
T.californica - has very high organisation in the tissue, to allow it to kill its prey by electric shocks
What domains does Agrin have and why?
ECM binding domain
Protein binding domain
For adhesion
What do Agrin KOs form?
Malformed NMJs
In the hippocampus, what happens if apply Agrin antisense mRNA?
Reduces the amount of hippocampal synapses
What experiment was done to see what the function of Agrin was?
What did this show?
Apply antibodies to neural Agrin - stoped clustering
Apply antibodies to muscle Agrin - doesn’t stop clustering
Show that it is the Agrin from NEURONS which induces clustering
Where does Agrin secreted from the nerve bind to?
MUSK (muscle-specific kinase) on the muscle
What is the structure of MUSK?
Has different complexes:
1) RATL (Rapsyn-associated transmembrane linker)
2) MASC (myotube-associated specificity component)
Where is MUSK made?
In the post-synaptic muscle target
Which complex on MUSK binds to AchR?
RATL
What happens in a MUSK KO?
Lose ability to cluster AchR
What is rapsin required for?
Clustering
What is required for intracellular signalling?
Receptor clustering + electrical activity
Do synapse change through development? Why?
Yes, synapses changing thought to be involved in memory
Why is important to have refined synaptic connections?
To produce circuits
What are climbing fibres and what happens to them during development?
Neuronal synapses on purkinje cells
In development: go from 4 –> 1 climbing fibre pre PC
What is the process of climbing fibre reorganisation?
- Initially, multiple CF innervate PC soma
- One PC selected through activity, to strengthen connections with PC
- This strenghtened PC, shifts its connections, from the soma, to the dendrites
- Weaker connections stay around the soma
- Connections around the soma are killed off
- One CF which is left has multiple connections to the dendrite
What does the neurotransmitter choice of a neuron depend upon?
The environment of the cell body of the neuron
What happens when an adrenergic cell body is implanted into a cholinergic neuron site and vice versa?
Neurons switch the neurotransmitters they produce, so that the parasympatheic neuron is now adrenergic and the sympathetic neuron is now cholinergic
In rat sweat glands, how does the innervation change?
Changes from adrenergic to cholinergic between P7 and P21
What happens if transplant footpad tissue into adrenergic innervation area?
Switches innervation from cholinergic to adrenergic
What are ‘silent synapses’?
Mature synapses (have all the machinery to work) but where there is no electrical activity (non-functional)
Where are ‘silent synapses’ found?
In NMJs and glutaminergic systems
In mature and developing nervous systems
Which synapse is crucial for memory?
What occurs at this synapse?
Glutamenergic synapse in CA1 in the hippocampus
Schaffer collaterals received at this synapse, from CA3 region of the hippocampus
What can activate ‘silent synapses’?
What does this form?
What is this called?
Tectanic stimulation (very high frequency stimulation)
Froms a stronger synapse
Long-term potentiation
How long does tectanic stimulation enhcance activity in a synapse for?
Minutes to years, depending upon the circuitry involved
How does tectanic stimulation turn on/strengthen synapses?
- Glutamate receptors in the synapse are initially blocked at resting potential, with Mg2+
- High frequency stimulation drags the Mg2+ out of the glutamate receptors
- This activates the receptors and causes calcium release
- Ca2+ upregulates AMPA - unblocks the synapse and makes it electrically active (no Mg2+ block)
What happens if synapses are not used?
They are lost
When does synapse formation/modification finish?
It doesn’t, it goes on throughout life
