Cell death

Cell death

1. ~ 50% neurons lost in development

   • Other cell types die too
   • Most death is deliberate

2. Where does it occur?

   • Everywhere
     • E.g.DRG's
       • DRG’s innervating limbs show less death
         • Trophic support
           • ?
     • E.g. motorneurons
       • Still cell death even though target tissue is increasing
         • Death occurring during synaptogenesis
           • Reflects competition
   • Pre and post synaptically
     • e.g. somatosensory barrels
     • e.g. chick auditory system
       • nucleus magnocellularis
       • nucleus laminaris
     • Matching cell death

3. How does it occur?

   • Most cells die through apoptosis
     • Programmed cell death
     • Active process
       • Inhibited by actinomycin D (transcription)
       • Or cycloheximide (protein synthesis)
     • Pro and anti apoptotic influences
       • Multiple, opposing genes involved with apoptosis
         • In C.elegans ced - 3 and ced - 4 required
         • Anti-apoptotic genes e.g. ced-9 (bcl-2)
     • Triggers for development apoptosis
       • Lack of trophic support
         • Neurotrophin supply (retrograde, anterograde, autocrine)
         • Transmitters can be trophic factors
           • Glutamate receptor (NMDA) activation
             • MK801 injection P7 forebrain
             • Other NMDA antagonists effective (e.g. paediatric anaesthetics)
               • Other transmitter ligands not
               • NMDA block – apoptosis ↑
             • Where receptors are matters
               • Hippocampus in vitro
                 • NMDA receptors synaptic and non-synaptic
                   • STAU evokes apoptosis
                     • Reduced by blocking GABA (bicucculine)
                   • Synaptic receptors are anti-apoptotic
                   • Extrasynaptic receptors are pro-apoptotic
       • Absence of depolarising stimulus
         • e.g. anterograde transport of NT3 in retinal ganglion neurons
         • e.g. early DRG’s in cell culture release NT3 and promote self differentiation
       • NGF deprivation
         • NGF withdrawal from sympathetic ganglion neurons in vitro
         • SGN have p75NTR, TrkA, LOW TrkC
         • Low NGF + KCl + BDNF (p75NTR, TrkB) = apoptosis
       • NT’s give pro and anti-apoptotic signals
         • An individual neuron needs both the “correct” NT’s and the absence of “wrong” NT’s
         • An axon in the wrong hood is in danger
           • Find the GIF
   • Roles for proneurotrophins too?
     • Synthesized in prepro form
       • Pre portion is signal peptide
       • Pro portion cleaved after release
     • PRO NGF strongly activates p75NTR
       • so the levels of enzymes to cleave PRO NGF are important too
       • growth cones can release cleavage enzymes
     • Release
       • Basal release
       • Stimulated release
         • depends on Ca2+
         • triggered by depolarization or ligand binding, e.g. other NT
       • More efficient synapse, more stimulated release, more binding / uptake by membrane recycling, more pre-synaptic effect?
         • More target more release.

4. Cleaning up the mess

   • Tidy removal of dying cells by macrophages
   • Plus neuritic disintegration and removal

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