LEC 35 and 36
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What kind of interactions guide synapse specificity in the retina?
Where do RGCs in the retina get their signals from?
Different bipolar cells in the inner plexiform layers
What kind of RGCs exist in the inner plexiform layers of the retina?
On and off centered cells
What kinds of signals do on/off center cells respond to?
Increases and decreases in light
What happens during the initial activity of the mature retina?
- Drives connection between bipolar cells and RGCs
- Helps define RGCs projection in the tectum
What happens to cells that are firing together and to the same stimuli? What happens to non-specific axons?
- Similar cells gather in the same area
- Non-specific cells prune away
Describe the interactions between bipolar cells and RGCs.
- Form synapses b/c of homophilic interactions
- Drives attraction btwn axons and post-synaptic targets
What does ORN stand for?
Odorant receptor neurons
What kinds of neurons innervate glomeruli?
ORNs expressing the same odorant receptor innervate the same glomeruli
Where are odorant receptors located?
On the axons of ORNs
What happens when there are no/deleted/different receptors on an ORN?
Innervate multiple random glomeruli
What happens when you switch the receptors of an ORN axon?
Innervate different glomeruli
What do the experiments with the projections of ORN axons show?
That odorant receptors are necessary and sufficient to influence the target of projection
How is AP patterning during immature olfactory axon targeting regulated?
By intrinsic activity of receptor cAMP signaling
What is the innate activity of olfactory cAMP signals?
- Intrinsic and spontaneous firing of GPCR olfactory receptor
- Activity isnt derived from receptor binding
What does high innate GPCR activity lead to?
- High cAMP signaling
- High CREB and PKA activity
- High Nrp1 receptor levels in growing axon
- Low sema3a expression in growing axon
What does low innate GPCR activity lead to?
- Low cAMP signaling
- Low CREB and PKA activity
- Low Nrp1 receptor levels in growing axon
- High sema3a expression in growing axon
Describe how the levels of Nrp1 and sema3a will define where along the AP axis the immature olfactory axon goes.
- High cAMP and Nrp1 levels- moves more posteriorly
- Low cAMP and high sema3a- stays more anteriorly
How is DV patterning determined in the olfactory system?
The placement of ORNs in the olfactory epithelium
Which mechanisms/gradients influence targeting along the DV axis?
Repulsive ligands [sema3f (D) and slit (V)] and receptors [Nrp2 (V) and Robo2 (D)]
Which mechanisms/gradients influence targeting along the ML axis?
Which mechanisms/gradients influence targeting along the AP axis?
Receptor activity-dependent regulation of guidance receptor [cAMP and Nrp1 (P)] expression
What does Nrp stand for?
What is neuronal activity in the olfactory system caused by?
- Stimuli driven by olfactory receptor activation
- Not the same as innate activity
What is needed for more exact placements of ORNs in glomeruli?
Need to start relying on neuronal activity
What happens when there is a high amount of neuronal activity in mature ORNs?
Drives kirrel2 and EphA5 expression
What happens when there is a low amount of neuronal activity in mature ORNs?
Drives Kirrel3 and ephrinA5 expression
What effect does the amount of olfactory neuronal activity have?
- Neurons from the same family will have almost exactly the same amount of neuronal activity because they have the same receptors
- They will produce the same amt of signaling proteins
How do kirrel proteins interact with each other?
Homophilic interactions attract them to each other
How do ephrin and Eph interact with each other?
They repel each other
How do the attractant and repellant factors affect targeting glomeruli?
- All axons from the same class express the same amount of an attractant (Kirrel proteins), so they are attracted to each other.
- And they all express the same amount of a repellent to other axons (Ephrins and EphRs), so theyll avoid bundling with non-similar ORNs to the same degree.
What needs to happen for a synapse to form?
There needs to be changes in both the growing axon and the receiving cell
What kind of pre-synaptic changes/specializations need to occur for there to be a synapse?
- Vesicle clustering
- NT synthesis and release
- Cytoskeleton changes
- Formation of active zones
- Concentration of mitochondria in the pre-synapse
What kind of post-synaptic changes/specializations need to occur for there to be a synapse?
- Clustering of receptors and scaffolding proteins
- Morphological changes (in the post-synaptic density [CNS] and membrane involutions [NMJ])
What is the best studied system for synapse formation?
Neuromuscular junction (NMJ)
What is another name for large membrane involutions?
What is the benefit of the large membrane involutions in muscle cells?
Give greater surface area to pack in a bunch of ACh receptors to respond to nerve impulse that make muscle contract
What are the two programs happening at once in the NMJ?
- Motor neurons are being specified (LIM homeodomain code), extending axons out, finding target, start reaching target in the muscle
- From target side- have myoblasts (precursors to muscle cells) that initially have a single nucleus. Make muscle from myoblasts by fusing to make larger cell that has multiple nuclei (myotube).
What are myoblasts?
Precursors to muscle cells
Where do myogenic precursors come from?
Where do motor axons come from?
Ventral part of spinal cord
What is myotube?
- Single cell with multiple nuclei
- Come from fusion of multiple myoblasts
What is myofiber?
Collection of myotubes
How many discrete steps are there for synapse formation?
What are the first and second steps for synapse formation?
- A growth cone finds and approaches a newly formed myotube
- Forms a morphologically unspecialized but functional contact
What is significant of the 2 structures (MN and muscle cell) during steps 1 and 2 of synapse formation?
- So far are relatively undifferentiated
- But still express many things that'll eventually make up the specialization (nAChRs in the post synaptic terminal and synaptic vesicles in the presynaptic terminal)
What happens during step 3 of synapse formation?
- The terminal accumulates synaptic vesicles and a basal lamina forms in the synaptic cleft
- Receptors start to accumulate around the nerve terminal
What happens during step 4 of synapse formation?
- As the muscle matures, multiple axons converge on a single site
- Schwann cell starts to wrap around the NMJ
What happens during step 5 of synapse formation?
All axons but one are eliminated and the survivor matures
What are the initial events in synaptogenesis?
- Growth cone in spinal motor neuron can release ACh before a synapse exists
- Muscle fibers have AChRs before innervation by motor neurons
- AChR density is uniform along the fiber
What happens when you deliver a piece of muscle and touch an electrically stimulated growth cone and record?
- Initially not much for the first 10 minutes
- Then there's an increase in frequency and amplitude
- This is b/c of reorganization of pre and post synaptic components
What is choline acetyltransferase?
Enzyme that synthesizes ACh
What are the on channels that allow for vesicle release?
- K channels
- Ca channels
- Snap 25
What do immature microtubes still express on their cell surface?
- ACh in low levels
- But distributed over entire surface
What does labeling AChRs on muscle cells with alpha-bungratoxin show?
Redistribution of AChRs following innervation
What can you label AChRs with to show redistribution of AChRs following innervation?
Alpha-bungratoxin from snake venom
What does the labeling of AChRs with bungratoxin demonstrate?
- Shows the presence of nicotinic receptors early
- They become concentrated underneath the synaptic terminal as differentiation continues
What three things trigger a redistribution of AChRs near the synapse after nerve innervation?
- Redistribution of the already present AChRs
- An activation of AChR transcription close to the synaptic region
- An inactivation of AChR transcription away from the synaptic region
What is the increase and decrease of transcription dependent on?
What kind of nerve/muscle activity affects the extrajunctional AChR density?
- Cutting nerve or blocking AChR function leads to maintenance of high extrasynaptic density
- Stimulating muscle represses transcription and reduces extrasynaptic density
What does neuregulin do?
Secreted into synaptic space and stimulates synthesis of AChRs at synaptic regions
What are neuregulins receptors?
What happens to erbBk under the terminal?
Goes through a series of intermediate players
What happens when you activate erbBk?
Activates expression of nAChR subunit genes
What happens to AChRs before they end up in the membrane?
Their RNA is transported out of nucleus, translated, protein made in golgi, and then inserted locally in the membrane where it was originally synthesized
What happens when theres less neuregulin?
Less AChRs at synapse
What is agrin?
Large extracellular matrix proteoglycan that is released by MN
What is agrin responsible for?
Protein responsible for the aggregation of already present AChRs
How does agrin aggregate AChRs at the NMJ?
- Agrin interacts with Lrp4
- Which activates MuSK
- Which phosphorylates Rapsyn
- Which clusters receptors
What is MuSK?
Muscle-Specific tyrosine Kinase
What can cause a fail to cluster AChRs
Agrin, Lrp4 and MuSK knockout mutants
What is the role of basal lamina in organizing MN terminals?
Tells us there was something special in the extracellular matrix (basal lamina) junctional area that's instructing differentiation of post syn structure
How did we know the basal lamina had a special role in organizing MN terminals?
- When a junction was initially made, there was stuff left behind in the basal lamina that looks different and induces presynaptic specialization
- Even after nerve was cut and muscle cell was killed
Whats the role of laminins in the basal lamina?
- Keeps things organized
- Different in junctional and extrajunctional areas
- Schwann cell would invade junctional areas too much
What are innervation-induced changes in embryonic AChR properties?
- Low conductance and long opening time
- Slow synaptic current
- Mobile, diffusely distributed
- Short half life
What are innervation-induced changes in mature AChR properties?
- High conductance and short opening time
- Fast synaptic current
- Stable, clustered
- Long half life
What kind of muscle fiber motor units exist in the immature organism?
What kind of muscle fiber motor units will increase in the maturing organism?
What defines the type of muscle fibers they will become?
The firing of motor neurons onto the fibers
What happens if you induce tonic firing onto muscle fiber?
Increase slow twitch muscle fibers
What happens if you induce phasic firing onto muscle fiber?
Get fast twitch muscle fibers
What needs to happen for differentiation into pre and post synapse to occur?
- Specific signaling at synaptic site from synaptic adhesion molecules
- Like Cadherin, neuroligin, and B-neurexin
What does neuroligin in kidney cells do?
Can promote presynaptic differentiation in neurons
What happens when axons come across developing dendrites?
Send out filopodia out of shaft
What does the protein PSD-95 do?
Keeps proteins organized on post synaptic side
What does the interaction between neuroligin in the post synaptic side and beta-neurexin in the presynaptic side do?
What is a HEK cell?
Human embryonic kidney cell
What happened to kidney cells expressing neuroligin?
Started growing structures that looked like synapses
What did they label kidney cells with?
Glutamate receptors on the postsynaptic site will start to cluster around the presynaptic sites that contain what?
GABA receptors on the postsynaptic site will start to cluster around the presynaptic sites that contain what?
What do the inhibitory glycine or gaba receptors require for clustering?
What do the excitatory receptors like glutamate and NMDA require for clustering?
Why is glia important for synapses?
Promotes formation of functional synapses
What happens in mature muscle fibers in terms of innervation by motor neurons?
- A muscle fiber will be innervated by just one motor neuron
- Although a motor neuron can innervate multiple muscle fibers
What happens to the neurons that were outcompeted for the spot on the muscle?
- Losing neurons dont die
- Just retract their axons
What are the steps that are taken to reduce the number of axons on a muscle?
- First, axon terminals segregate
- Then, the losing neurons withdraw their axons
What happens when you remove some motor neurons? Why?
- All muscle fibers still innervated
- Crazy competition
What happens when you remove the original innervation? Why?
- Other motor neurons take over
- Crazy competition
What is TTXs original function?
- Blocks Na channels and action potentials
- Inhibits activity
What happens when you add TTX to a muscle fiber?
- Blocks elimination
- Same muscle fiber innervated by multiple neurons
Where is there a reduction of AChR?
In the synapse that will be eliminated at the muscle
What happens when there is a reduction of AChRs?
- Reduce activity of synapse
- Leads to axonal retraction
What are the 3 possible mechanisms/hypotheses of synaptic competition?
- Trophic factor hypothesis
- Toxic factor hypothesis
- Synaptomedin hypothesis
What is the trophic factor hypothesis?
- The motor neurons that are more active are going to receive more maintenance factors from the synaptic site
- SynaptoTROPHINS promote survival
- Inactive terminals dont receive this trophic factor
What is the toxic factor hypothesis?
- Elimination due to muscle derived toxic substance
- Active nerve terminals become immune
- Protease inhibitor slows down elimination process
What is the synaptoMEDIN hypothesis?
- Local factors (synaptomedins) are released at the synaptic site onto nerve terminals
- Selectively stabilize active nerve terminals
- Destabilizing inactive nerve terminals
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