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 December 20, 2007
Citation Information: J Clin Invest. 2008;118(1):272-280. https://doi.org/10.1172/JCI33009.
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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 4

Leptin selectively inhibits the AMPAR-mediated component of the CA1 field excitatory postsynaptic potentials (fEPSPs) in mouse hippocampal slices.

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Leptin selectively inhibits the AMPAR-mediated component of the CA1 fiel...
(A) Leptin inhibited the AMPAR component of the CA1 fEPSP. Time course of the fEPSP slope for the AMPAR component after bath-applied 0.6 nM leptin as indicated by the bar (n = 4 slices, 2 mice). The AMPAR component was isolated by adding the N-methyl-d-aspartate (NMDA) antagonist D-APV (50 μM) as indicated by the bar. (B) In contrast, leptin did not inhibit the NMDAR component of the CA1 fEPSP. Time course of the fEPSP slope for the NMDA component after bath-applied 0.6 nM leptin as indicated by the bar (n = 6 slices, 4 mice). The NMDAR component was isolated by adding the AMPAR antagonist CNQX (10 μM) in Mg2+-free ACSF. Data in A and B were analyzed as in Figure 3B. The bars indicate when Mg2+-free ACSF and leptin were applied. (C and D) Leptin enhances paired-pulse facilitation. (C) Superimposed representative pairs of CA1 fEPSPs from the same slice demonstrate fEPSP inhibition and increased paired pulse facilitation in 0.6 nM leptin (arrows). Interstimulus interval: 25 ms; calibration: 4 ms, 0.2 mV. (D) Cumulative data from 5 slices (5 mice) comparing the paired pulse facilitation ratio (PPF = P2/P1, where P1 is the slope of the first fEPSP and P2 is the slope of the second fEPSP) before and after the application of 0.6 nM leptin for 20 minutes (*P < 0.02, paired t test).