NEUR3001 Lecture Notes - Lecture 5: Zinc Finger, Bassoon, Spacetime
Trans-Synaptic Signalling & Synaptic Adhesion:
Molecular Mechanisms of Synapse Formation
1. Neuromuscular Synapse Formation as a Model Synapse
• Mechanism of synaptic plasticity
• Understanding neurodegenerative diseases
• Mechanism of neural repair
• NMJ biggest synapse and simple → excitatory, only Ach NT
• Successful re-innervation at synapse
2. Bi-directional Exchange of Signals during Synapse Formation
2.1. Morphological Changes at Developing NM Synapse
a) Growth cone projects towards target (developing skeletal muscle)
b) Growth cone makes initial contact with surface of skeletal muscle →
accumulation of synaptic vesicles
c) Transformation from growth cone to nerve terminal →
accumulation of AChR under nerve terminal
d) Further development of nerve terminals → polyneuronal
innervation → ↑AChR accumulation
e) Loss of polyneuronal innervation → one pre-synaptic terminal per
muscle fibre (weaker and inactive terminal removed by Schwann cell)
Synaptic loss characterised by:
- Initial loss of post-synaptic receptors (AChRs)
- Down-regulation of muscle GF release to motor nerve terminal
- Schwann cell remodelling to remove inactive terminals
2.2. Bi-directional Molecular Signalling: Motor nerve ↔ Muscle
I. Neural-Agrin & Neuregulin-β1 → Induce post synaptic gene
expression
II. Synaptic laminins → induce adhesion, synaptic stability &
synaptic specialisations
- MND: NMJ disassembly occurs in early stages
- Ageing: Loss of post-synaptic AChRs precedes loss of nerve terminals
3. Molecules Mediating Synaptic Cross-Talk in Basal Lamina
• Holds in place molecules for adhesion and GF
• Represents muscle health → Breakdown = dystrophy
• Coats muscle fibres
3.1. Muscle-Basal Lamina Ghost Experiment
Indicates that synaptic BL traps secreted signalling molecules (i.e. Fibroblastic GF binding protein 4 FGFB4 needed for
synapse formation
3.2. Torpedo Electric Organ (TEO)
• Isolated signalling molecules in BL due to its vast amount of synaptic BL
• Injecting Ab for molecules found in synaptic BL into animal OR
• Immunostaining NMJ → see if molecules located or not at NMJ
• Isolate laminin, AChR, GRP etc
Occurs during reconnections post-
injury & is affected in NM diseases
(i.e. myasthenia gravis & MND)
Synaptic BL
Irradiated Nerve terminal →
nerve terminal grows back
at correct junction
Irradiated muscle → muscle
grows back with AChR
density concentrated at
original site
4. In-vitro Bioassays to Determine Function of Molecule
- Test synaptic vs non-synaptic BL
- Ab (block events)
- Molecules that work downstream of signalling molecules
4.1. Growth Cone → Nerve Terminal (Pre-synaptic Differentiation)
• Recap in-vitro event
• When GC contacts muscle → differentiates to nerve terminal (morphological changes)
- Extra-synaptic BL → β1-laminin in muscle
- Synaptic BL → β2-laminin in TEO
Neuron in middle (either differentiates to
terminal or keeps growing as it does not
recognise β1 → not involved in pre-synaptic diff)
Formation of nerve terminals from growth cone
Neuron
Muscle
Document Summary
Down-regulation of muscle gf release to motor nerve terminal. Schwann cell remodelling to remove inactive terminals. Neural-agrin & neuregulin- 1 induce post synaptic gene expression. Synaptic laminins induce adhesion, synaptic stability & synaptic specialisations. Occurs during reconnections post- injury & is affected in nm diseases (i. e. myasthenia gravis & mnd) Mnd: nmj disassembly occurs in early stages. Ageing: loss of post-synaptic achrs precedes loss of nerve terminals: molecules mediating synaptic cross-talk in basal lamina, holds in place molecules for adhesion and gf, represents muscle health breakdown = dystrophy, coats muscle fibres. Indicates that synaptic bl traps secreted signalling molecules (i. e. fibroblastic gf binding protein 4 fgfb4 needed for synapse formation. Irradiated nerve terminal nerve terminal grows back at correct junction. Irradiated muscle muscle grows back with achr density concentrated at original site. Isolated signalling molecules in bl due to its vast amount of synaptic bl. Injecting ab for molecules found in synaptic bl into animal or.
