FIGURE 7.

A hypothetical scheme to explain how CP-AMPARs may contribute to heterosynaptic LTP and heterosynaptic metaplasticity. (A) A spaced theta burst (sTBS) induction protocol (to input 1), as described in Park et al. (2018), induces LTP2 on the homosynaptic input (LTP1 will also be induced, not shown). (B) Spread of Ca²⁺ and cAMP (or PKA), generated during the sTBS, to proximal independent inputs triggers local de novo protein synthesis. This leads to (i) heterosynaptic LTP2 and (ii) heterosynaptic metaplasticity. Since protein synthesis has already been triggered, this component of metaplasticity is not affected by inhibitors of CP-AMPARs or protein synthesis. (C) At more distal synapses, the spread of cAMP (or PKA), but not Ca²⁺, leads to the insertion of CP-AMPARs into the perisynaptic membrane. wTBS can drive these CP-AMPARs into the synapse and trigger heterosynaptic metaplasticity, via the triggering of local de novo protein synthesis. As such, this component of metaplasticity is sensitive to inhibitors of CP-AMPARs and protein synthesis.