Systematic Elimination

Systematic Elimination

1. Neuromuscular Junction Formation

   • 1. Clustering of polysynaptic receptors under nerve-muscle contact
     • Triggered by agrin deposited in basal lamina
   • 2. Agrin in BL binds to MuSK (muscle-specific kinase) in muscle cell membrane
   • 3. MuSK communicates with rapsyn
     • Rapsyn gathers postsynaptic Ach Receptors at synapse
   • 4. Size of receptor group regulated by Neuregulin
     • Stimulate receptor gene expression in muscle cell
   • 5. Induction of presynaptic targets involve proteins in basal lamina
     • ErB(2,3,4)
     • RAS
     • RAF
     • MAPK
   • 6. Stimulated Ca2+ entry into growth cone
     • AchR synthesis

2. Elimination of synapses

   • Hebbian Modifications
     • If cell A close enough to cell B to excite it and take part in firing it
       • Growth process or metabolic change takes place to increase cell A's efficiency
     • Cells that fire together, wire together
     • Cells that fire out of synchronicity lose their link

3. Views on axodendritic synapse formation

   • "Caveman courtship" view
     • Axon + growth cone finds dendrite
       • Induces postsynaptic specialisations
         • Evolves into presynaptic terminal
     • Axon = active, dendrite = passive
       • WRONG!
         • Many times, dendritic spines initiate "seeking out" axons

4. Differentiation

   • Presynaptic bouton
     • Clustering of synaptic vesicles (SVs)
     • Formation of active zones
       • Regions of plasma membrane with electron-dense meshes of cytoskeleton, where SVs dock and fuse
     • Neuroglins bind to b-neurexins
       • Induces formation of presynaptic specialisations
     • Accomplished not via sequential molecule recruitment
       • Instead by insertion of pre-assembled macromolecular complexes
   • Postsynaptic region
     • Formation of postsynaptic density (PSD)
       • Electron-dense cytoskeletal matrix juxtaposed to active zone
         • Cluster and localise NT receptors to post-synaptic membrane
     • Postsynaptic differentiation = sequential

5. Plasticity

   • Homeostatic plasticity
     • = Process of stabilising developing neural network
       • Deal with dramatic increase of number of excitatory synapses
     • Global changes in
       • Synaptic transmission
       • Intrinsic properties
       • Plasticity threshold
       • Excitation-inhibition balance
       • Spontaneous activity
   • Coding plasticity
     • Local changes in synaptic transmission and connectivity
   • Steps for dealing with synaptic configuration
     • 1. Modify intrinsic neuronal excitability
     • 2. Scale synaptic strengths
     • 3. Regulate relative balance of excitation and inhibition received by neuron
       • 4. Regulate threshold for plastic modifications in input-specific manner

6. Apoptosis

   • Neurotrophins
     • Members
       • NGF = Nerve growth factor
       • BNDF = Brain-derived neurotrophic factor
       • NT-3 and NT-4/5
     • Function
       • Bind to low afinity receptor (p75) and to tyrosine kinases (Trk)
     • Effects on neurones
       • Promotion of differentiation
       • Promotion of survival during development