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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
Citation Information: J Clin Invest. 2008;118(1):272-280. https://doi.org/10.1172/JCI33009.
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Categories: Research Article Neuroscience

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

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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 6

Leptin inhibits low magnesium–induced spiking in cultured mouse hippocampal neurons.

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Leptin inhibits low magnesium–induced spiking in cultured mouse hippocam...
(A) Whole-cell patch recordings from cultured hippocampal neurons in current clamp configuration spontaneously fire action potentials in nominally magnesium-free external solution. Baseline membrane potential: –57 mV. Calibration for A1–A3: 10 s, 30 mV. (B) Leptin (1 nM) reduces action potential firing frequency by 30%–40%. (C) Action potential firing recovers close to baseline frequency after leptin washout. (D) Cumulative data comparing spike frequency in low magnesium before (filled squares) and after (open squares) application of different leptin concentrations. Each filled and open symbol connected by a line represents 1 cell and its firing frequency before and after leptin. Therefore, each line represents 1 matched data pair; some data points are superimposed on each other. The mean ± SD values are presented beside each data set with a larger symbol. A significant reduction in spike frequency was produced by 1.0 nM (n = 13 cells) and 10 nM (n = 11 cells), but not by 0.1 nM (n = 12 cells) leptin (paired t test).
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ISSN: 0021-9738 (print), 1558-8238 (online)

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