Abstract

Neuromodulation can profoundly impact the gain and polarity of postsynaptic changes in Hebbian synaptic plasticity. An emerging pattern observed in multiple central synapses is a pull-push type of control in which activation of receptors coupled to the G-protein Gs promote long-term potentiation (LTP) at the expense of long-term depression (LTD), whereas receptors coupled to Gq promote LTD at the expense of LTP. Notably, coactivation of both Gs- and Gq-coupled receptors enhances the gain of both LTP and LTD. To account for these observations, we propose a simple kinetic model in which AMPA receptors (AMPARs) are trafficked between multiple subcompartments in and around the postsynaptic spine. In the model AMPARs in the postsynaptic density compartment (PSD) are the primary contributors to synaptic conductance. During LTP induction, AMPARs are trafficked to the PSD primarily from a relatively small perisynaptic (peri-PSD) compartment. Gs-coupled receptors promote LTP by replenishing peri-PSD through increased AMPAR exocytosis from a pool of endocytic AMPAR. During LTD induction AMPARs are trafficked in the reverse direction, from the PSD to the peri-PSD compartment, and Gq-coupled receptors promote LTD by clearing the peri-PSD compartment through increased AMPAR endocytosis. We claim that the model not only captures essential features of the pull-push neuromodulation of synaptic plasticity, but it is also consistent with other actions of neuromodulators observed in slice experiments and is compatible with the current understanding of AMPAR trafficking.