Figure 3.

The molecular pathways of heterosynaptic potentiation and depression. A Simplified representation of the molecular pathways through which homosynaptic potentiation (center spine) can drive heterosynaptic depression (H-LTD, left spine) and heterosynaptic potentiation (H-LTP, right spine) of neighboring synaptic spines. At the central spine, presynaptic glutamate release activates postsynaptic AMPA and NMDA receptors. NMDA receptor activation leads to calcium entry into the synapse, which in combination with calmodulin leads to CaMKII activation. CaMKII activation results in the activation of Ras and RhoA1, and in combination with TrkB activation through BDNF also the activation of Cdc42 and Rac1. Both CaMKII and BDNF activation may also result in the local translation of Arc mRNA present from previous bouts of activity. While activated Cdc42 remains confined to the activated spine, Ras, RhoA1, Rac1, and Arc spread along the dendritic shaft with the potential to interact with neighboring spines. If a nearby spine is inactive (left), Arc is recruited to the spine by an interaction with inactive CaMKIIβ. Small influxes of calcium, insufficient to activate CaMKII, can activate calcineurin. Release of proBDNF by the activated spine, in the absence of MMP9, can also result in binding of proBDNF to p75 neurotrophin receptors (p75NTR). Each of these processes can promote either structural spine shrinkage or the endocytosis of surface AMPA receptors, leading to H-LTD. If a neighboring synapse is instead activated (right, activation either simultaneous with or following the center spine), MMP9 promotes cleavage of proBDNF to BDNF which binds to TrkB receptors. This, in combination with NMDA receptor driven CaMKII activation, leads to Cdc42 activation. Cdc42 activation by a subthreshold stimulus, in combination with the spread of activated Ras, RhoA1, and Rac1 from the center synapse, drives the remodeling of the actin cytoskeleton leading to structural H-LTP. CaMKII, Ca²⁺-calmodulin-dependent protein kinase II; MMP9, matrix metalloproteinase 9. Image assets reproduced from smart.servier.com (Servier Medical Art, 2015) (CC-BY).