Tuesday, April 1, 2014

Synaptic plasticity part 2

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