What are the morphological changes that occur when a growth cone turns into a pre-synapse?
- Filopodia retraction & tight junction formation
- Membrane + extracellular glycoproteins added
- Presynaptic vesicles, dense ECM, receptors in cleft
What is the difference between immature pre-synapse with an adult synapse?
- Few and only small vesicles in the newborn
- Narrow cleft between cells
- Thicker post synaptic density in the adult
What other parts of the axons can initiate synapses other than growth cones?
- Axon branches
- Dendritic filopodia
When does synaptogenesis happen?
- As axons reach their targets
- Varies greatly between regions
- Spinal cord, brainstem and other regions become functional pre-brith
- Most cortical synapses (cortex) are created after birth
How can non-neuronal neighbours shape synapses?
- RIA axons synapse with AIY interneurons but only at specific points
- Sheath cells (glia) secrete netrins which ventrally guide RIA axons
- Netrin also causes its receptor to cluster in the AIY neurons, promoting assemble of pre-synaptic terminals
What are Neurexins and neuroligins?
- Synapse cell adhesion molecules
- Each have a large family and bind to a member from the other
- large intracellular domains to assemble intracellular components into the active zone and post synaptic density
What allows synapses to be both inhibitory and excitatory on the same cell?
- differential expression of the multiple members of the neurexin and neuroligin families allows different presynaptic neurons to select between post-synaptic partners
- Differential localisation of neuroligins of the postsynaptic cell also allows separated innervation by excitatory and inhibitory presynaptic neurons
Give an example of a cell with multiple different connections that are spatially segregated
- Purkinje cell
- Plasticity in connections that can be remodelled over time
What are the three models of synapse/spine formation?
- Dendritic spines develop largely independently of pre-synaptic inputs
- Presynaptic inputs induce spine formation
- Dendritic filopodia induce synapses in axons that are growing pase (also called en passant synapses)
How does the assembly of synaptic components occur?
- Axon-dendrite contact triggers intracellular signals
- Contact mediated through Neurexins and neuroligins
- Soluble factors released by pre/post synaptic cell promote recruitment of scaffolding proteins which provide a framework for the formation of protein complexes that form active zone + post synaptic density
What are examples of the scaffolding proteins for pre and post synaptic cells?
CASK = presynaptic
PSD-95= post-synaptic
What is the postsynaptic density?
Region in postsynaptic membrane which plays a role in signalling, plasticity and structure
Its electron dense
Why is the neuromuscular junction used in studies widely?
It is huge and simple
What is the contact of the incoming motor neuron important for and how?
- Important for assembling components of the synapse
- Innervation leads to progressive clustering of Acetylcholine receptors under nerve terminal
How does receptor clustering work?
- Motor neurons secrete AGRIN which induces new AChR clusters on cultured myotubes
- pre-clusters do form in immature myotubes though which suggests post-synaptic cell may direct the innervation
What are the stages of receptor clsutering?
- Initially AChRs expressed at low levels (shown by low level mRNA) in myotube nuclei
- As motor neuron comes in it releases agrin which binds to MuSK on myotube (Muscle specific Kinase)
- Auto-phosphorylates and recruits Rapsyn which in turn recruits and clusters AChRs
- ACh is also released and can bind to and activate AChRs both in and away from the nerve terminal
5.When this is not accompanied by agrin signalling it inhibits AChR expression in non-synaptic nuclei
AGRIN + ACH RESULTS IN MORE ACH RELEASE
ACH ON ITS OWN IT INHIBITS ACHR EXPRESSION
Describe some knockout experiments involved with the stages of receptor clustering
Ach KO= AChR clusters grow faster and larger
MuSK KO= no AChR preclusters and no neuromuscular junctions, insensitive to agrin
Rapsyn KO = Lack AChR pre-clusters and neuromuscular junctions
