Home NEUR 310 Thursday, January 16, 2014

Thursday, January 16, 2014 CC-BY-NC
Neuronal Cell Survival and Cell Death

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1Apoptosis

  • cell and nuclear shrinkage
  • condensation of chromatin and fragmnetation of DNA
  • phagocytosis of cellular remains
  • cytoplasmic vacuolation
  • different from necrosis : from injury and rapid cellular lysis

1.1neurons apotosis

  • number of neurons present at different times during development first indicated that many neurons were first overproduced and subsequently lost

  • chick embryo experiment

    • increasing the size of limb target reduces motorneuron deaths

    • blocking muscle activity with curarae : prevent death of motoneurons

    • neurotrophic factor hypothesis:

      • target keep neurons alive. More motorneurons were born and those that don't receive trophic factors die.
      • trophic factor : NGF
        • discovered in mouse sarcoma tumor which produced hypertrophy of chick nervous system
        • increase sprouting and survival of chick sensory ganglion
        • a complex of 3 gene products
          • beta homodiomer: trophic activitiy
        • locally controls neuritic growth, as demonstrated in cultural dish w compartments

2Neurotrophic factors#

  • other trophic factors : BDNF, NT3, NT3/4
  • trks : trasnmembrane tyrosine kinase that are receptors for neurotrophins
    • trkA: NGF and NT3
    • trkB: BDNF, NT3, NT4/5
    • trkC: NT3
  • trk signaling
    • dimerize and self-phosphorylate via SH2 domain and signal transduction
    • recruits Shc -> Grb -> Sos -> Ras -> MAP kinase cascade (Raf -> MEK -> ERK)
      • injecting activated ras, raf or MEK into neurons generate a similar effect as NGF

  • p75 : binds w all the neurotrophic factors

    • promote cell death via its death domain

  • neurotrophin promotes cell survival via

    • phospholipase C gamma and posphotidylinositol-3-kinase
    • Akt activation --> Bcl2 --| apoptosis
      • bcl2 (ced-9 in C elegans) block apaf1 (Ced-4)
      • Apaf1 leads to caspase activation and apoptosis

  • neurotrophin signaling:

    • axonal sprouting: locally
    • cell survival and other changes in gene expression: retrograde transport to cell body
    • combination of several trophic factors rae required to keep a cell alive

2.1Steroid Hormones

  • contains zinc finger motif to bind to DNA sequence called HRE (hormone response elements)
  • rats
    • males have bigger SDN-POA (dimorphic nucleus of the preoptic area) because testosterone acts as a trophic factor
    • extrogen receptor mediates the effect of testosterone
  • song birds:
    • RA and HVA nuclei for song learning: bigger in males during mating season than in females
    • due to circulating testosterone