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 - 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)
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 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 Binds and activates receptor tyrosine kinases on the muscle (erbB2, erbB3, erbB4) Signals through MAP-kinase pathway
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 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
Dostları ilə paylaş: |