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Mutations that alter signaling through the mammalian target of rapamycin complex 1 (mTORC 1 ), a well established regulator of neuronal protein synthesis, have been linked to autism and cognitive dysfunction. Although previous studies have established a role for mTORCl as necessary for enduring changes in postsynaptic function, here we demonstrate that dendritic mTORCl activation in rat hippocampal neurons also drives a retrograde signaling mechanism promoting enhanced neurotransmitter release from apposed presynaptic termi-nals. This novel mode of synaptic regulation conferred by dendritic mTORCl is locally implemented, requires downstream synthesis of brain-derived neurotrophic factor as a retrograde messenger, and is engaged in an activity-dependent fashion to support homeostatic fraiis-synaptic control of presynaptic function. Our findings thus reveal that mTORCl-dependent translation in dendrites subserves a unique mode of synaptic regulation, highlighting an alternative regulatory pathway that could contribute to the social and cognitive dysfunction that accompanies dysregulated mTORCl signaling. [ABSTRACT FROM AUTHOR]

Summary: Homeostatic synaptic plasticity is important for maintaining stability of neuronal function, but heterogeneous expression mechanisms suggest that distinct facets of neuronal activity may shape the manner in which compensatory synaptic changes are implemented. Here, we demonstrate that local presynaptic activity gates a retrograde form of homeostatic plasticity induced by blockade of AMPA receptors (AMPARs) in cultured hippocampal neurons. We show that AMPAR blockade produces rapid (<3 hr) protein synthesis-dependent increases in both presynaptic and postsynaptic function and that the induction of presynaptic, but not postsynaptic, changes requires coincident local activity in presynaptic terminals. This “state-dependent” modulation of presynaptic function requires postsynaptic release of brain-derived neurotrophic factor (BDNF) as a retrograde messenger, which is locally synthesized in dendrites in response to AMPAR blockade. Taken together, our results reveal a local crosstalk between active presynaptic terminals and postsynaptic signaling that dictates the manner by which homeostatic plasticity is implemented at synapses. [Copyright &y& Elsevier]