LTP

LTP

1. Hebbian synapse

   • "Coordinated activity of a presynaptic terminal and a postsynaptic neuron strengthen the synaptic connections between them"

2. The hippocampus

   • Alzheimers hits hippocampus early
   • Circuit
     • Entorhinal to dentate (perforant)
     • Dentate to CA3 (mossy fibres)
     • CA3 to CA1 (Schaffer collaterals)
     • Output via fornix and subiculum
     • The hippocampal slice
       • Read the papers

3. The phenomenon

   • Usually CA3 to CA1 synapses
   • High frequency stimulus (HFS –resembles human θ rhythm) produces a long-lasting potentiation
   • Shows input specificity
   • Shows co-operativity (co-incidence), which does not need HFS
     • Two pathways converging on the same target can both be strengthened if they fire together.
       • One pathway may be quite weak
       • Associative
     • May be a result of NMDA receptor properties
       • NMDA receptors have a voltage-dependent Mg2+ block.
         • So, NMDA receptors need to be indirectly pre-activated by a separate depolarising input

4. How does it occur

   • LTP could occur by pre-synaptic changes.
     • Evidence suggests often a post-synaptic event.
   • Most indicates a critical role for Ca2+

5. Early and late

   • Early
     • Some essential aspects of LTP occur early and do not require protein synthesis.
     • NMDAR - mediated Ca2+ ↑ activates calmodulin kinase II (CaMKII)
       • PSD protein (2-5%)
         • Or is it PKC?
           • KO / inhibition studies conflicting
       • Multiple catalytic subunits
       • Autophosphorylation and constant activation triggered by Ca2+ in LTP
         • Phosphorylation enhances AMPA currents.
           • Barria et al 1997
     • May involve AMPAfication
       • The delivery of ready-prepared AMPA receptors to the synapse
       • Does this mimic synaptic development?
   • Late
     • Some are late and do.
       • Long-term storage needs protein synthesis
     • Takes effect ≈ 1 hour after initiation
     • cAMP signaling may be critical

6. Is LTP memory?

   • There are different types of synapses and LTP
     • Mossy fibre – CA3 LTP is non-NMDA and mainly presynaptic
       • ↑ transmitter release Ca2+ activated / cAMP mediated
     • Perforant path – dentate gyrus does not use CamKII
     • LTP varies in non-hippocampal areas, e.g. cortex
   • There are different types of memory
     • The hippocampus is mainly new and declarative in function
     • Episodic
     • Semantic
     • Spatial recognition
   • LTP is linked to memory
     • Inhibiting LTP inhibits some memory formation
       • AP5 and Morris water-maze – time-critical effect
     • Mutations of CaMKII, NMDARs, cAMP pathway all affect aspects of learning
     • Drugs to enhance memory (nootropics) also enhance LTP
       • AMPAkines - Alzheimer’s – poor success.
         • Read up about
     • LTP isnt everything about memory
       • LTP is only necessary for some memory formation, it is not sufficient
       • AND LTP is a phenomenon linked to LTD, which can be a related form of plasticity

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