Leptin Induces a Novel Form of NMDA Receptor-Dependent LTP at Hippocampal Temporoammonic-CA1 Synapses

Leptin-induced LTP at TA-CA1 synapses involves a postsynaptic expression mechanism. A, Plot of pooled and normalized data illustrating the effects of 100 nm (15 min) leptin on excitatory synaptic transmission evoked at TA-CA1 synapses. Calibration: 0.1 mV, 20 ms. B, Corresponding plot of the pooled PPR against time for the experiments shown in A. The effects of leptin on synaptic transmission were not accompanied by any significant change in PPR. In contrast, the synaptic depression induced by DA is accompanied by a significant alteration in PPR. Above the plots are representative pairs of fEPSPs evoked with a 50 ms interstimulus interval at the times indicated.

NMDA receptor activation is required for leptin-induced LTP at TA-CA1 synapses. A–D, Plots of pooled and normalized data illustrating the effects of leptin (100 nm; 15 min) on TA-CA1 fEPSP slope in juvenile hippocampal slices. In control conditions (A) application of leptin resulted in LTP, whereas in the presence of d-AP5 (50 μm; B), leptin failed to alter excitatory synaptic strength. C, D, Selective blockade of GluN2B subunits with either ifenprodil (3 µm; C) or Ro 25-6081 (3 µm; D) also prevented leptin-induced LTP. Calibration: 0.2 mV, 100 ms.

Leptin-induced LTP involves a PI 3-kinase-dependent process. A, B, Plots of pooled and normalized data illustrating the effects of leptin on synaptic transmission in the presence of the PI 3-kinase inhibitor LY294002 (10 μm; A) or the ERK inhibitor U0126 (10 μm; B), respectively. Leptin-induced LTP was prevented following blockade of PI 3-kinase, but not ERK. Calibration: 0.2 mV, 100 ms. C, Histogram of the pooled data showing the relative effects of leptin (100 nm) on synaptic transmission in control conditions and in the presence of either LY294002 (10 μm), wortmannin (50 nm), U0126 (10 μm), or PD98059 (10 μm).

An increase in the synaptic density of GluR2-lacking AMPA receptors underlies leptin-induced LTP. A–C, Plots of pooled and normalized data illustrating the effects of leptin on synaptic transmission in control conditions (A), and in the presence of 1 μm philanthotoxin, the GluA2-lacking AMPA receptor inhibitor, applied either 15 min before (B) or immediately after (C) leptin addition. Prior treatment with philanthotoxin completely prevented leptin-induced LTP (B), whereas the leptin-driven increase in synaptic transmission was reversed by philanthotoxin. Calibration: 0.2 mV, 100 ms. D, Histogram of the pooled data showing the relative effects of leptin (100 nm) on synaptic transmission alone and in the presence of philanthotoxin (1 µm) applied before leptin application, immediately after leptin application, or 30 min after leptin washout.

Activity-dependent synaptic plasticity at TA-CA1 synapses has a postsynaptic expression mechanism and is NMDA receptor dependent. A–C, Plots of pooled and normalized data illustrating the effects of the HFS paradigm (arrow) on excitatory synaptic transmission in control conditions (A), and in the presence of the competitive NMDA receptor antagonist d-AP5 (50 μm; B) or the selective GluN2B antagonist Ro-256981 (3 μm; C). Histograms of the pooled data showing the relative effects of the HFS paradigm on synaptic transmission in control conditions and in the presence of either d-AP5 (50 μm), ifenprodil (3 μm), or Ro-256981 (3 μm). E, Plot of pooled and normalized data illustrating the effects of HFS on excitatory synaptic transmission evoked at TA-CA1 synapses. F, Corresponding plot of the PPR against time for the experiments shown in E. HFS-induced LTP at TA-CA1 synapses is not accompanied by any significant change in PPR. Calibration: 0.2 mV, 100 ms.

An ERK-signaling process underlies HFS-induced LTP at TA-CA1 synapses. A–C, Plots of pooled and normalized data illustrating the effects of the HFS paradigm (arrow) on excitatory synaptic transmission in control conditions (A) and in the presence of the ERK inhibitor PD98059 (10 mm; B) or the PI 3-kinase inhibitor LY294002 (10 mm; C). Calibration: 0.2 mV, 100 ms. D, Histograms of the pooled data showing the relative effects of the HFS paradigm on synaptic transmission in control conditions and in the presence of either PD98059 (10 μm), U0126 (10 μm), LY294002 (10 μm), or wortmannin (50 nm). Blockade or ERK, but not PI 3-kinase, activity prevented HFS-induced LTP.