Lecture 15: Synapse Formation Flashcards
What structure sends signals to overlaying ectoderm to signal neural tissue formation?
- Notochord
- “causes formation”
What happens after the formation of the neural tube?
- Neurogenesis
What do neural cells most commonly follow in neural migration?
- Radial glial fibres
What determines which target cells to innervate?
- Cell-cell attractions
- Cues to drive attractive forces
Is the process of synaptogenesis rigid or flexible?
- Generally very flexible
- Some restrictions
What are the restrictions on synaptogenesis?
- No synapses with glial cells in CNS
- No synapses with connective tissue in PNS
What are the 3 stages in forming synaptic connections?
- Initiation
- Induction (with chemical signals)
- Reinforcement (strengthening/growth or synaptic pruning/apoptosis)
When does synaptogenesis begin?
- Once an axon reaches its target region
How precise is initiation of synaptogenesis?
- Imprecise
- Guided by graded system of preferences (not absolute)
What does initiation of synaptogenesis consist of?
- Recognition b/n proteins on pre- and post-synaptic cells
What makes potential connections b/n potential pre-and post-synaptic sites?
- Share many molecules
- Includes many adhesion molecules that participate in axon guidance (cadherins, protocadherins)
What is the initiation of synaptogenesis mediated by?
- CAMs (cell adhesion molecules; cadherins, protocadherins)
What do CAMs do in the initiation of synaptogenesis?
- Link pre- and post-synaptic domains as proteins recognized
What is there initially an accumulation of in the initiation of synaptogenesis?
- Synaptic vesicles and transport vesicles that contain molecular components of presynaptic active zone
What is induction in synaptogenesis?
- Construct architecture to maintain synapse
What is the role of CAMs in induction?
- Elaborate on cellular specialization
- Form structural components of the synapse by recruiting cytoskeletal proteins to form synaptic shape
- Localize synaptic vesicles
- Cluster postsynaptic receptors
What are 5 inductive factors?
- SynCAM
- Ephrin B/EphB-R
- Neurexin
- Neuroligin
- Neuregulin
Where are neurexins and what do they do?
- In presynaptic membrane
- Specialized transmembrane domain helps localize vesicles, docking proteins and fusion molecules
- Localizes voltage-gated Ca2+ channels vital for vesicle release
Where are neuroligins and what do they do?
- In postsynaptic membrane
- Interact with specialized postsynaptic proteins to promote clustering of receptors/channels of postsynaptic density
- Maximize synaptic signalling
Where is neuregulin 1 found and what does it do?
- Made in synapse, cleaved, then acts on postsynaptic ErbB receptors
- Regulates expression and localization of other postsynaptic receptors (human NRG1 gene associated with schizophrenia)
What does the interaction of neurexin with neuroligin do?
- Central for recruiting and retaining cytoskeletal elements that localize synaptic vesicles to the presynaptic terminal and mediate their fusion
- Ensure post-synaptic membrane has proper receptors available
- Shared by all developing synapses
What are genetic polymorphisms of neurexin or neuregulin related to?
- Autism and schizophrenia
- Dysfunction in these CAMs can affect entire CNS
What are some likely players in synaptic identity/differentiation?
- DSCAM1
- Ephrin ligands and receptors
- Other CAMs
- Mutation effects
- Protocadherins
What effect is DSCAM1 thought to have on differentiation?
- Similar process that mediates dendritic tiling may prevent a cell from forming synapses with itself
- Chemorepellant signals to keep a space
What effect are ephrin ligands/receptors thought to have on synaptic identity?
- Diverse population may be differentially distributed
- Cell-cell recognition
When it comes to synaptic identity, what are CAMs thought to do?
- Multiple sites for alternative transcript splicing can encode many variants of the same basic protein with differential distribution
What effects might mutations have on synaptic identity?
- Unexpected
- Subtly disrupted connectivity patterns
What might protocadherins do in synaptic differentiation?
- A diverse array of CAMs arising from a single gene
- Not uniformly expressed in neighbouring synaptic sites
- Adherence/affinity relies on degree of similarity b/n proteins and neighbouring cells
What kind of scale are synapses formed on?
- Probability
What is the reinforcement of synaptogenesis dependent upon?
- Trophic interaction b/n pre- and post-synaptic cells (apoptosis vs. growth)
What do neurotrophic factors do in reinforcement of synaptogenesis?
- Secreted in relatively small quantities from target tissues
- Regulate differentiation, growth, and survival in nearby cells
- Don’t diffuse far, so they are hard to identify
What are 4 neurotrophins involved in the reinforcement of synapses?
- Nerve growth factor
- Brain derived neurotrophic factor
- Neurotrophin 3
- Neurotrophins 4 and 5
What is an example of a role that nerve growth factor (NGF) plays in reinforcement?
- Elicits robust growth of neuronal processes (neurites) on sympathetic neurons
What is an example of BDNF’s function in reinforcement?
- Supports survival of sensory ganglion cells
What role might NT-3 play in reinforcement?
- Supports sympathetic and ganglion neurons (combination of NGF and BDNF)
What might NT-4/5 support in reinforcement?
- Neurite extension on cerebellar neurons
What does the neurotrophin excreted depend on?
- Synaptic identity/differentiation
When in life do axons synapse onto more target cells?
- Birth (more than maturity)
What happens to immature contacts? Why?
- Removed with development
- Leaving a focus on fewer target cells
- Progressively increasing amount of synaptic machinery for each axon that remains
- Creates a stronger connection
Describe the developing nervous system?
- Initial surplus of cells
- Limited trophic support
What happens to cells that fail to interact successfully with targets?
- Undergo apoptosis
- Regulated process that results in cell death
- Mediated by neurotrophic factors
How can a population of afferent neurons be appropriately matched to its target? List 3 assumptions.
- Neurons depend on a minimum amount of neurotrophic factor for survival and connections
- Target tissues synthesize appropriate trophic factors and make them available to developing neurons
- Survival, persistence, differentiation of developing neurons are subjective to interneuronal competition for available factor
What happens when chick sensory ganglion cell is incubated in absence of NGF?
- Minimal neuronal branching/process outgrowth
Describe trophic factors in general
- Similar function
- Encoded by distinct genes
- Act in different places (ex. dorsal root ganglia vs. nodose ganglia vs. sympathetic ganglia)
Where does NGF promote neurite growth?
- Dorsal root ganglia
- Sympathetic ganglia
- NOT nodose ganglia
Where does BDNF promote neurite growth?
- Dorsal root ganglia
- Nodose ganglia
- NOT sympathetic ganglia
Where does NT-3 promote neurite growth?
- Dorsal root ganglia
- Nodose ganglia
- Sympathetic ganglia
How are neurotrophins similar to neurotransmitters?
- Neurotrophins activate receptors
- Receptors influence action of neurotrophins
- Only have function in trophins act on receptors
What do specific Trk receptors have a high affinity for?
- Processed (proteolytic cleavage) neurotrophins
What do p75 receptors have a high affinity for?
- Unprocessed neurotrophins
- Low affinity for processed
What likely contributes to specificity of neurotrophic interactions?
- Very specific cell neuronal expression and localization
What kind of receptors are neurotrophic receptors?
- Metabotropic (trigger G protein)
- Transmembrane domains, NOT ion channels
How do filopodia/lamellipodia guide the growing process?
- They adhere to substrates in extracellular environment
- Respond to guidance cues
Is a certain chemical always seen as a chemorepellant?
- No, it may be a chemoattractant for another growth cone
What do cells compete for in order to survive?
- Formation of adequate synapses
- Trophic factors
