Leptin is a protein hormone that primarily regulates feeding behaviour and energy expenditure in the central nervous system. Recent studies have discovered a role for leptin in modulating hippocampal synaptic plasticity at hippocampal CA1 synapses via activating postsynaptic NMDA receptors. In particular, leptin induces a long-term (P5-8) or transient (P11-18) depression of synaptic transmission that depends on GluN2B subunit-containing NMDA receptors in juvenile hippocampus, whereas leptin evokes long-term potentiation that depends on GluN2A subunit-containing NMDA receptors in the adult hippocampus. Moreover, NMDA receptor subunits are heterogeneously distributed along the apical dendrites of CA1 pyramidal neurons, such that GluN2B-lacking NMDA receptors selectively concentrate at distal dendritic region of pyramidal cells where they receive direct cortical input (perforant path) from the entorhinal cortex. Indeed, mounting evidence demonstrates that the direct cortical input is of importance to spatial learning and memory. Here we show that application of leptin induced a novel form of long-term potentiation (LTP) of excitatory synaptic transmission at perforant path (PP) to CA1 synapses with normal inhibitory synaptic transmission in juvenile hippocampus. The LTP evoked by leptin exhibited concentration dependence, as treatment with a low concentration of leptin (1nM) had no effect on excitatory synaptic transmission, whereas perfusion of high concentrations of leptin (25-100nM) induced LTP of excitatory synaptic transmission that increased to ~20%. Furthermore, leptin-driven LTP had a postsynaptic locus of expression and depended on the activation of GluN2B-subunit containing NMDA receptors. In addition, the leptin-driven LTP shared similar mechanism with classical activity-dependent LTP at PP-CA1 synapses, as both process required the activation of GluN2B -containing NMDA receptors and partially occluded each other. Our results indicate that leptin plays a pivotal role in modulating NMDA receptor dependent synaptic plasticity at PP-CA1 synapses in juvenile hippocampus.
|Date of Award
|Andrew Irving (Supervisor) & Jenni Harvey (Supervisor)
- Perforant path
- Synaptic plasticity
- NMDA receptor