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

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

• 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 (-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