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 -/-: 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 |
| 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
| Overall structural similarities | |
| Bi-directional signaling | |
| Clustering of neurotransmitter receptors | |
| Synaptic vesicles have similar components | |
| Synapse elimination during development |
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 (g-aminobutyric acid) and glycine | ||
| different neurotransmitter receptors | ||
| 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 |