Synapse formation completes the wiring of the nervous system Birth and differentiation of neurons...
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Transcript of Synapse formation completes the wiring of the nervous system Birth and differentiation of neurons...
![Page 1: Synapse formation completes the wiring of the nervous system Birth and differentiation of neurons Extension of axons/axon guidance Target recognition Synaptic.](https://reader033.fdocuments.in/reader033/viewer/2022051622/56649eb75503460f94bc1137/html5/thumbnails/1.jpg)
Synapse formation completesthe wiring of the nervous system
• Birth and differentiation of neurons
• Extension of axons/axon guidance
• Target recognition
• Synaptic differentiation and signaling between nerve cells
• Refinement of circuits and experience-dependent modifications
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Synapse Formation in the Peripheral and Central
Nervous System
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Synapses: the basic computation unitsin the brain
• Human brain consists of 1011 neurons that form a network with 1014 connections
• The number and specificity of synaptic connection needs to be precisely controlled
• Changes of synaptic connections and synaptic strength are the basis of information processing and memory formation
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Aberrant synaptic connectivityand synaptic function lead to disease states
• Loss of synapses in Alzheimer’s disease
• In epilepsy excessive synapse formation and synaptic misfunction are observed
• Genes associated with mental retardation and schizophrenia have synaptic functions
• Paralysis after spinal cord injuries
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Central Synapses andNeuromuscular Junctions (NMJs)
• Neuron-neuron and neuron-muscle synapses develop by similar mechanisms
• NMJs are larger, more accessible and simpler than central synapses therefore the molecular mechanisms of synapse formation are best understood for the NMJ
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Structure of the neuromuscular junction
• Mature NMJs consist of three cell types– Motor nerve– Muscle cell– Schwann cells
• All three cell types adopt a highly specialized organization that ensures proper synaptic function
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Nerve terminal:- rich in synaptic vesicles- active zones- mitochondria- axon are rich in neurofilamentsand contain only few vesicles
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Muscle:- junctional folds opposing the active zones- specific cytoskeleton at synapse- strong concentration of ACh-R
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Schwann Cells:- thin non-myelin processes thatcover nerve terminal- myelin sheet around the remainingaxon from exit site from the spinalcord to the NMJ
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Basal Lamina:- present at synaptic andnon-synaptic regions, but specificmolecular composition at synapse(e.g.: acetylcholinesterase in cleft)
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vesicles
neurofilament
ACh-receptors
overlay
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General Features of Synapse Formation
1) The pre- and post-synaptic cell organize each others organization (bi-directional signaling)
2) Synapses mature during development– widening of synaptic cleft, basal lamina– transition from multiple innervation to 1:1
3) Muscle and nerve contain components required for synaptogenesis (vesicles, transmitter, ACh-R) “reorganization”
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Stages of NMJ Development
- growth cone approaches
- non-specialized but functional contact
- immature specializations
- multiple innervation
- elimination of additional axons, maturation
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Clustering of ACh-R: A) Aggregation of existing receptors
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Clustering of ACh-R: B) Local synthesis of receptors
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Denervation and muscle elimination(but preservation of muscle satellite cellswhich will form new myotubes)
In the absence of nerve, ACh-Rs clusterat the original synaptic site
The basal lamina directsclustering of ACh-Rs
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Cultured muscle fiber
Cultured muscle fiber + agrin
Agrin
• Component of the basal lamina
• 400 kDa proteoglycan
• Secreted from motor neuron and muscle
• Neural form potently induces clustering of ACh-Rs in myotubes
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Agrin signals through MuSK
• agrin interacts with a MuSK/Masc on the muscle• MuSK is a receptor tyrosine kinase• MuSK activation leads to phosphorylation of rapsyn and clustering of ACh-Rs
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Wild type Agrin mutant
MuSK mutant Rapsyn mutant
Mouse mutants confirmessential roles for agrin, MuSK, rapsyn
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Summary of mutant phenotypes
• Agrin -/-: few ACh-R clusters, overshooting of axons• MuSK -/-: no ACh-R clusters, overshooting of axons• Rapsyn -/-: no ACh-R clusters, but higher receptor
levels in synaptic area, only limited overshooting
• Pre-synaptic defects in all mutants, due to the lack of retrograde signals from the muscle
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A) Aggregation of existing receptors
B) Local synthesis of receptors
AgrinMuSKRapsyn
???
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Neuregulin (ARIA)
• Acetylcholine receptor inducing activity
• Expressed in motor neuron and in muscle
• Binds and activates receptor tyrosine kinases on the muscle (erbB2, erbB3, erbB4)
• Signals through MAP-kinase pathway
• Leads to upregulation of ACh-R expression in sub-synaptic nuclei
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Decrease in ACh-R inneuregulin (+/-) heterozygous mice
Wild type Heterozygote
MEPP(miniatureexcitatorypotential)
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Clustering of ACh-R: B) Local synthesis of receptors
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Neural activity represses ACh-R synthesis in non-synaptic areas
Paralysis
ElectricalStimulation
Extra-synaptic ACh-Rtranscription increased
Extra-synaptic ACh-Rtranscription decreased
Extra-synaptic ACh-Rtranscription increased
Extra-synaptic ACh-Rtranscription decreased
Denervation
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Three neural signals for the induction of postsynaptic differentiation
• Agrin: aggregation of receptors in the muscle membrane
• Neuregulin: by upregulation of ACh-R expression in sub-synaptic nuclei
• ACh/neural activity: downregulation of ACh-R expression in extra-synaptic nuclei
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Denervation
Regeneration
Denervation +Muscle elimination
Regeneration
Components of the basal laminacan organize the nerve terminal
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Laminin 11 affects presynaptic differentiation
Wild type Laminin2 mutant
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Synaptic inactivity can leadto synapse elimination
pre
post
post
pre
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Pre-synaptic terminal:Synaptic vesiclesPre-synaptic cytomatrixActive zone
Synaptic cleft:20 nm wide, filled withelectron-dense material(proteins and carbohydrates)
Post-synaptic compartment:Spine structure Dense submembrane scaffoldNeurotransmitter receptors
Structure of excitatory synapses in the CNS
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Analogies of central synapses and NMJs
• Overall structural similarities
• Bi-directional signaling
• Clustering of neurotransmitter receptors
• Synaptic vesicles have similar components
• Synapse elimination during development
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Differences between central synapses and NMJs
• No basal lamina• No junctional folds but dendritic spines• Multiple innervation is common• Difference in neurotransmitters:
– Excitatory synapses use glutamate– Inhibitory synapses use GABA (-aminobutyric
acid) and glycine
• different neurotransmitter receptors
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Cytoplasmic scaffolding proteins mediateclustering of receptors in the CNS
PSD95clustersglutamatereceptors
Gephrynclustersglycinereceptors
• One neuron can receive excitatory and inhibitory inputsthrough different synaptic connections• Transmitter in presynaptic vesicles is matched with thepostsynaptic receptors
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Direct trans-synaptic interactions in the CNS
cadherinsneuroligin/neurexin
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Neuroligin can inducepresynaptic differentiation in CNS neurons
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Direct trans-synaptic interactions in the CNS
cadherinsneuroligin/neurexin
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Future directions/problems
• Many factors that mediate synaptic differentiation in the CNS are not understood
• Target specificity
• Regeneration after injury is very low in CNS compared to PNS resulting in paralysis
• Strategies to improve re-growth of axons and specific synapse formation