Insulin induces a novel form of postsynaptic mossy fiber long-term depression in the hippocampus

The mechanisms of induction and the site of expression of long-term depression (LTD) at the hippocampal mossy fiber-CA3 synapses are not clear. Here, we show that a brief bath application of insulin induces a novel form of mossy fiber LTD. This insulin-LTD is (1) induced and expressed postsynaptically, (2) entirely independent of synaptic stimulation during insulin application, (3) involving a rise in postsynaptic [Ca(2+)](i) and L-type voltage-activated Ca(2+) channel activation, (4) mechanistically distinct from low-frequency stimulation-induced LTD, (5) dependent on phosphatidylinositol 3-kinase signaling, and (6) associated with a clathrin-mediated endocytotic removal of surface 3-hydroxy-5-methylisoxazole-4-propionic acid receptors from the postsynaptic neurons. Moreover, insulin-LTD is specific to mossy fibers to CA3 pyramidal cell synapses, and is not present at associational commissural synapses. These findings not only support a postsynaptic locus of mossy fiber LTD, but also provide a further link between the AMPA receptor trafficking and the bidirectional expression of long-term synaptic plasticity.