LTD at mossy fiber synapses onto stratum lucidum interneurons requires TrkB and retrograde endocannabinoid signaling.

Hippocampal mossy fiber axons simultaneously activate CA3 pyramidal cells and stratum lucidum interneurons (SLIN), the latter providing feedforward inhibition to control CA3 pyramidal cell excitability. Filopodial extensions of giant boutons of mossy fibers provide excitatory synaptic input to the SLIN. These filopodia undergo extraordinary structural plasticity causally linked to executing memory tasks, leading us to seek the mechanisms by which activity regulates these synapses. High frequency stimulation of the mossy fibers induces LTD of their calcium permeable-AMPA receptor synapses with SLINs; previous work localized site of induction to be postsynaptic and site of expression to be presynaptic. Yet the underlying signaling events and the identity of the retrograde signal are incompletely understood. We used whole cell recordings of SLIN in hippocampal slices from wild type and mutant mice to explore the mechanisms. Genetic and pharmacologic perturbations revealed a requirement for both the receptor tyrosine kinase, TrkB, and its agonist, BDNF, for induction of LTD. Inclusion of inhibitors of Trk receptor kinase and phospholipase C in the patch pipette prevented LTD. Endocannabinoid receptor antagonists and genetic deletion of the CB1 receptor prevented LTD. We propose a model whereby release of BDNF from mossy fiber filopodia activates TrkB and PLCg1 signaling postsynaptically within SLINs, triggering synthesis and release of an endocannabinoid that serves as retrograde signal, culminating in reduced glutamate release. Insights into the signaling pathways by which activity modifies function of these synapses will facilitate understanding their contribution to the local circuit and behavioral consequences of hippocampal granule cell activity.