Tuesday, April 1, 2014 CC-BY-NC
Synaptic plasticity part 2

Maintainer: admin

1LTP : Long term synaptic plasticity

  • required for memory and learning
  • forming stable neural connection

  • Hebb synapse: cells fire together are wired together

    • cell A firing to cell B : both are strenghten
  • often use hippocampus to do research since it's the basis for memory and learning

    • guy with hippocampus removed: can't formed more declarative memory
    • mossy fiber from dentate gyrus projects to CA3 pyramidal cells, which project to CA1 cells
      • this wiring allows sticking electrode into the brain and track the responses
  • LTP not only causes bigger response in strenghten neurons, but also decrease failure rate (i.e. neurons more likely to release vesicles when stimulated)

1.1LTP requirements

  • strong stimulation of an input leads to LTP of that input
  • LTP is specific : while one synapse strengthens, the other one doesn't
  • associative : synapses that fire at the same time get strengthened together

    • pairing presynaptic activity with post-syanptic depolarization also induces LTP
      • i.e. you depolarize the postsynaptic cell while stimulating it, it can help induce LTP
  • LTP requires NMDA receptor

    • blocking it leads to no LTP
    • NMDA receptor is blocked by Mg2+,
    • gutamate from presynaptic terminal binds to it
    • however, really need depolarization to unplug the magnesium, the channel opens, and then Ca2+ enter the cell, this leads to LTP
      • evidences: activating calcium buffer "photolabile" with flash photolysis reduces LTP
        • i.e. if you take away calcium right after stimulation you don't get LTP
  • LTP requires CamKII

    • CamKII, a 5 unit molecule, autophosphorylate itself when Ca+ binds
    • so at high Calcium concentration, it's constitutively active (completely phosphorylated)
    • it then phosphorylates AMPA receptor and increase their conductance
      • however, not the major reason for LTP because the increas is too small
  • LTP require increase AMPA-Rs responses

    • this is mediated through NMDA
    • NMDA signal downstream to increase number of AMPA at the synapse
      • therefore it can "unsilent" the silent synapses (don't have AMPA-Rs and only have NMDA-Rs
      • silent synapses are common in early development
    • Mechanism of how NMDA receptors increase AMPA receptors
      • activate calcium-dependent kinases: CamKII, PKC
      • AMPAR phosphorylation
      • increase AMPA receptor numbers
        • experiment : auditory fear conditioning
        • resutlt and evidence with electrophysiological tagging
          • using viral expression of GluA , a subunit of AMPA receptor, to show that new AMPA receptors are synthesized
          • new AMPA receptors with viral GluA1 exhibit inward rectification
          • measuring inward current tells us there are new AMPA receptors
        • evidence with carboxy-terminal fragment of gluA1
          • this is a fragment of the unit, generating non-functional AMPA
          • result: animal can't form LTP (no fear-conditioning)

2Late phase LTP (L-LTP)

  • LTP : lasts 1-2 hours
  • L-LTP : last for days
    • requires protein synthesis (because it doesn't happen when you use inhibitor of protein synthesis)

2.1Mechanism of LLTP formation

  • CREB activation

    • Ca2+ from NMDA -> calmodulin -> protein kinases -> PKA -> CREB -> transcription and synapse growth proteins
    • CREB is always in nucleus and it's activated by phosphorylation and forms a dimer
    • once activated, it drives transcription of plasticity-associated genes
  • synaptic tagging

    • first stimulation leads to production of "goodies" (the stuff required for the strenghtened synapse, such as AMPA-receptor subunits)
    • second stimulation leads to tagging (which we don't know what)
      • "goodies" are sent to the synapses with the tags
    • how do we know this
      • blocking protein synthesis after the first stimulation allows LLTP to forms, but not before
    • the tags persist for about 2 hrs, after 4 hrs it's all gone
  • a second weak simulation which would normally leads to E-LTP can be converted to LLTP if the first one is a strong stimulation

2.2Structural changes

  • synaptic spines get bigger