Leptin inhibits 4-aminopyridine– and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents
Lin Xu, … , Michael Wong, Kelvin A. Yamada
Lin Xu, … , Michael Wong, Kelvin A. Yamada
Published January 2, 2008; First published December 20, 2007
Citation Information: J Clin Invest. 2008;118(1):272-280. https://doi.org/10.1172/JCI33009.
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Category: Research Article

Leptin inhibits 4-aminopyridine– and pentylenetetrazole-induced seizures and AMPAR-mediated synaptic transmission in rodents

Abstract

Leptin is a hormone that reduces excitability in some hypothalamic neurons via leptin receptor activation of the JAK2 and PI3K intracellular signaling pathways. We hypothesized that leptin receptor activation in other neuronal subtypes would have anticonvulsant activity and that intranasal leptin delivery would be an effective route of administration. We tested leptin’s anticonvulsant action in 2 rodent seizure models by directly injecting it into the cortex or by administering it intranasally. Focal seizures in rats were induced by neocortical injections of 4-aminopyridine, an inhibitor of voltage-gated K+ channels. These seizures were briefer and less frequent upon coinjection of 4-aminopyridine and leptin. In mice, intranasal administration of leptin produced elevated brain and serum leptin levels and delayed the onset of chemical convulsant pentylenetetrazole-induced generalized convulsive seizures. Leptin also reduced neuronal spiking in an in vitro seizure model. Leptin inhibited α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor–mediated synaptic transmission in mouse hippocampal slices but failed to inhibit synaptic responses in slices from leptin receptor–deficient db/db mice. JAK2 and PI3K antagonists prevented leptin inhibition of AMPAergic synaptic transmission. We conclude that leptin receptor activation and JAK2/PI3K signaling may be novel targets for anticonvulsant treatments. Intranasal leptin administration may have potential as an acute abortive treatment for convulsive seizures in emergency situations.

Authors

Lin Xu, Nicholas Rensing, Xiao-Feng Yang, Hai Xia Zhang, Liu Lin Thio, Steven M. Rothman, Aryan E. Weisenfeld, Michael Wong, Kelvin A. Yamada

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Figure 5

Leptin inhibits AMPAR-mediated EPSCs obtained from voltage-clamped CA1 pyramidal neurons in mouse hippocampal slices.

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Leptin inhibits AMPAR-mediated EPSCs obtained from voltage-clamped CA1 p...
(A) Representative tracings of Schaffer collateral evoked whole-cell EPSCs recorded from a voltage-clamped CA1 neuron at –70 mV at baseline during perfusion of ACSF containing 2 mM CaCl2 and 1 mM MgCl2 (Baseline), after a 10-minute perfusion with 0.6 nM leptin (Leptin), and after a 20-minute washout with ACSF (Recovery). Calibration: 5 ms, 25 pA. (B) Leptin inhibited AMPAR-mediated EPSCs with a U-shaped dose-response relation. Peak amplitudes of AMPAR-mediated EPSCs after a 10-minute perfusion with various leptin concentrations expressed as a percentage of the peak amplitude of the baseline EPSC (n = 5–9 cells). *P < 0.001 for 0.6 vs. 0.06 nM and *P < 0.01 for 0.6 vs. 50 nM leptin (ANOVA followed by Tukey-Kramer’s test for multiple comparisons). (C) Leptin-enhanced paired pulse facilitation. The paired-pulse ratio was calculated as in Figure 4 by using peak amplitudes of pairs of EPSCs evoked with an interstimulus interval of 25 milliseconds in 0.6 nM leptin. n = 8 cells, *P < 0.02 (paired t test).