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Maintenance and Synaptic stability

Maintenance and Synaptic stability The problem of stability given protein turnover and trafficking LTP, LLTP and protein synthesis Stability and synaptic specificity The molecular switch idea CaMKII as a molecular switch, lack of experimental evidence

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Maintenance and Synaptic stability

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  1. Maintenance and Synaptic stability • The problem of stability given protein turnover and trafficking • LTP, LLTP and protein synthesis • Stability and synaptic specificity • The molecular switch idea • CaMKII as a molecular switch, lack of experimental evidence • An alternative hypothesis – clusters of interacting receptors.

  2. Stable, synapse specific, synaptic plasticity: how can this be accomplished? Synaptic strengths can be expressed by protein number or state. For example number of AMPA receptors, or the phosphorylation state of AMPA receptors. However, such proteins and their specific conformational states have limited life times, much shorter than the life time of memories, or even of long term synaptic plasticity. One proposed solution, a molecular switch (Crick, Lisman)

  3. The calcium signal that leads to LTP is short, on the order of seconds, yet plasticity lasts a lifetime. • Phsphorylation • Dephosphorylation: What is phopsphorylated by Kinases, it typically dephosphorylated by phosphatases. • Protein turnover: Proteins have a limited lifetime (hours, possibly days), when a phosphorylated protein is elimiated and a new one generated, the new one will not be phosphorylated • Diffusion and trafficking: When proteins are phosphorylated in one synapse, they are likely to diffuse away, or be actively trafficked away.

  4. Insertion of synapses • Trafficking: receptors are rapidly trafficked into and away from spines. If the number is increased due to plasticity, it may re-equilibrate due to trafficking, diffusion and turnover.

  5. phosphatase phosphatase The most studied example auto-phosphorylation in CaMKII holoenzymes. • Problems • Molecular switches are bi-stable (binary) p p p • No solid experimental evidence

  6. The concept of bi-stability CaMKIIp [Ca]

  7. But actually (Bradshaw et al. 2003) Maybe it is bi-stable is cells

  8. So what could the stability mechanism be?

  9. Explain on board about L-LTP induction

  10. Fonseca et. al. 2006

  11. Late phase of LTP, LLTP is protein synthesis dependent. If we can turn on protein synthesis, we can make more of a given protein (say AMPA receptors), more or less permanently, overcoming the problem of turnover However: Protein synthesis is a whole cell processes, how can it effect different synapses differently in order to preserve synapse specificity. The synaptic tag hypothesis.

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