Synapse formation completes the wiring of the nervous system Synapse Formation in the Peripheral and Central Nervous System



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Synapse formation completes the wiring of the nervous system


Synapse Formation in the Peripheral and Central Nervous System



Synapses: the basic computation units in 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



Aberrant synaptic connectivity and 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





Central Synapses and Neuromuscular 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



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













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”




Clustering of ACh-R: A) Aggregation of existing receptors



Clustering of ACh-R: B) Local synthesis of receptors





Agrin



Agrin signals through MuSK





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





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







Clustering of ACh-R: B) Local synthesis of receptors



Neural activity represses ACh-R synthesis in non-synaptic areas



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





Laminin 11 affects presynaptic differentiation







Analogies of central synapses and NMJs



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















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




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