sign in sign up
<<
Home , Synaptogenesis

formation completes the wiring of the

• Birth and differentiation of Synapse Formation in the • Extension of axons/axon guidance Peripheral and Central • Target recognition • Synaptic differentiation and signaling Nervous System between nerve cells • Refinement of circuits and experience- dependent modifications

Synapses: the basic computation units Aberrant synaptic connectivity in the brain and synaptic function lead to disease states • Human brain consists of 1011 neurons that form a network with 1014 connections • Loss of in Alzheimer’s disease • The number and specificity of synaptic • In epilepsy excessive synapse formation and connection needs to be precisely controlled synaptic misfunction are observed • Changes of synaptic connections and • Genes associated with mental retardation synaptic strength are the basis of and schizophrenia have synaptic functions information processing and memory • Paralysis after spinal cord injuries formation

Central Synapses and Neuromuscular Junctions (NMJs) • -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

1 Structure of the

• Mature NMJs consist of three cell types Nerve terminal: - rich in synaptic vesicles –Motor nerve - active zones – - mitochondria – Schwann cells - axon are rich in neurofilaments and contain only few vesicles

• All three cell types adopt a highly specialized organization that ensures proper synaptic function

Muscle: Schwann Cells: - junctional folds opposing the - thin non- processes that active zones cover nerve terminal - specific cytoskeleton at synapse - myelin sheet around the remaining - strong concentration of ACh-R axon from exit site from the spinal cord to the NMJ

vesicles

Basal Lamina: - present at synaptic and neurofilament non-synaptic regions, but specific molecular composition at synapse (e.g.: acetylcholinesterase in cleft) ACh-receptors

overlay

2 General Features of Synapse Stages of NMJ Development

Formation - approaches 1) The pre- and post-synaptic cell organize each others organization (bi-directional signaling) - non-specialized but functional contact 2) Synapses mature during development - immature specializations – widening of synaptic cleft, basal lamina – transition from multiple innervation to 1:1 - multiple innervation 3) Muscle and nerve contain components required for synaptogenesis (vesicles, transmitter, ACh-R) - elimination of additional axons, Æ “reorganization” maturation

Clustering of ACh-R: Clustering of ACh-R: A) Aggregation of existing receptors B) Local synthesis of receptors

The basal lamina directs clustering of ACh-Rs • Component of the basal lamina Denervation and muscle elimination (but preservation of muscle satellite cells • 400 kDa proteoglycan which will form new myotubes) • Secreted from and muscle • Neural form potently induces clustering of In the absence of nerve, ACh-Rs cluster ACh-Rs in myotubes at the original synaptic site Cultured muscle fiber

Cultured muscle fiber + agrin

3 Mouse mutants confirm Agrin signals through MuSK essential roles for agrin, MuSK, rapsyn • agrin interacts with a MuSK/Masc on the muscle Wild type Agrin mutant • MuSK is a receptor tyrosine kinase • MuSK activation leads to phosphorylation of rapsyn and clustering of ACh-Rs

MuSK mutant Rapsyn mutant

Summary of mutant phenotypes A) Aggregation of existing receptors Agrin • Agrin -/-: few ACh-R clusters, overshooting of axons MuSK Rapsyn • MuSK -/-: no ACh-R clusters, overshooting of axons • Rapsyn -/-: no ACh-R clusters, but higher receptor levels in synaptic area, only limited overshooting B) Local synthesis of receptors • Pre-synaptic defects in all mutants, due to the lack of retrograde signals from the muscle ???

Neuregulin (ARIA) • 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

4 Decrease in ACh-R in (+/-) heterozygous mice Clustering of ACh-R: B) Local synthesis of receptors Wild type Heterozygote

MEPP (miniature excitatory potential)

Three neural signals for the induction Neural activity represses ACh-R of postsynaptic differentiation synthesis in non-synaptic areas • Agrin: aggregation of receptors in the muscle membrane Paralysis • Neuregulin: by upregulation of ACh-R

Extra-synaptic ACh-R Extra-synaptic ACh-R expression in sub-synaptic nuclei transcription decreased transcription increased Denervation • ACh/neural activity: downregulation of ACh-R expression in extra-synaptic nuclei Electrical Extra-synaptic ACh-R Stimulation transcription increased Extra-synaptic ACh-R transcription decreased

Components of the basal lamina Laminin 11 affects presynaptic can organize the nerve terminal differentiation

Wild type Lamininβ2 mutant

Denervation + Denervation Muscle elimination

Regeneration Regeneration

5 Synaptic inactivity can lead Structure of excitatory synapses in the CNS to synapse elimination

Pre-synaptic terminal: Synaptic vesicles pre Pre-synaptic cytomatrix post Synaptic cleft: 20 nm wide, filled with electron-dense material (proteins and carbohydrates)

pre Post-synaptic compartment: Spine structure Dense submembrane scaffold post receptors

Analogies of central synapses and NMJs Differences between central synapses and NMJs • Overall structural similarities • No basal lamina • Bi-directional signaling • No junctional folds but dendritic spines • Clustering of neurotransmitter receptors • Multiple innervation is common • Synaptic vesicles have similar components • Difference in : • Synapse elimination during development – Excitatory synapses use glutamate – Inhibitory synapses use GABA (γ-aminobutyric acid) and glycine • different neurotransmitter receptors

Cytoplasmic scaffolding proteins mediate Direct trans-synaptic interactions in the CNS clustering of receptors in the CNS

Gephryn PSD95 clusters clusters glycine glutamate receptors receptors

• One neuron can receive excitatory and inhibitory inputs through different synaptic connections • Transmitter in presynaptic vesicles is matched with the postsynaptic receptors / cadherins

6 Neuroligin can induce Direct trans-synaptic interactions in the CNS presynaptic differentiation in CNS neurons

neuroligin/ cadherins neurexin

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

7