Leptin inhibits rat hippocampal neurons via activation of large conductance calcium-activated K+ channels

Shanley, Lynne; Irving, Andrew J.; Rae, Mark G.; Ashford, M. L. J.; Harvey, Jenni

doi:10.1038/nn824

Cited by 80 publications

(116 citation statements)

References 10 publications

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“…In addition to the inhibition of AMPAR-mediated synaptic transmission, leptin's anticonvulsant effect may result from NMDAR inhibition (39) or BK channel activation (11,13,36). Our results are consistent with those of a model in which the inhibition of AMPAR-mediated synaptic transmission contributes to leptin's anticonvulsant effect at low (nanomolar) concentrations, and other mechanisms contribute at higher concentrations.…”

Section: Figuresupporting

confidence: 88%

“…Recent studies in primary neuronal cultures and hippocampal slices have characterized some of leptin's anticonvulsant properties beyond its role in regulating energy homeostasis. In these studies leptin suppressed epileptiform-like bursting and elevations in intracellular calcium under low extracellular magnesium conditions by opening large-conductance calciumactivated neuronal potassium (BK) channels (11,13,14). Leptin also induces long-term depression (LTD) under these conditions (15).…”

Section: Introductionmentioning

confidence: 99%

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

Xu¹,

Rensing²,

Yang³

et al. 2008

J. Clin. Invest.

108

104

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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 pentylenetetrazoleinduced 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.

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Section: Figuresupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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

Xu¹,

Rensing²,

Yang³

et al. 2008

J. Clin. Invest.

108

104

View full text Add to dashboard Cite

show abstract

“…Treating normal mice with leptin also seemed to increase the number of hypothalamic stem cells. This latter finding is consistent with the known stimulatory effects of leptin on neurogenesis in the hippocampus and the development of feeding circuits (5,18). The results generated by McNay et al using ob/ob mice further demonstrate that obesity affects the capacity for renewal of neurons in the arcuate nucleus (12); however, it remains unclear whether hypothalamic neurogenesis is directly regulated by leptin or whether indirect effects via alterations in the levels of glucocorticoids or insulin or various other metabolic defects impact hypothalamic neurogenesis in ob/ob mice (4).…”

Section: Obesity and Hypothalamic Neurogenesissupporting

confidence: 88%

Alteration of hypothalamic cellular dynamics in obesity

Lee¹,

Ahima²

2012

J. Clin. Invest.

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“…That insulin and leptin act on the same pool of neurons is further demonstrated by studies showing that both hormones inhibit large conductance calcium-activated potassium channels in a hippocampal slice preparation (58,59). However, leptin's effect on these channels is largely related to activation of PI3K, whereas the insulin effect appeared to be more dependent on mitogen-activated protein kinase activation.…”

Section: Insulin Leptin and The Control Of Neuronal Ion Channelsmentioning

confidence: 96%

Insulin Signaling in the Central Nervous System

2005

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Insulin and its signaling systems are implicated in both central and peripheral mechanisms governing the ingestion, distribution, metabolism, and storage of nutrients in organisms ranging from worms to humans. Input from the environment regarding the availability and type of nutrients is sensed and integrated with humoral information (provided in part by insulin) regarding the sufficiency of body fat stores. In response to these afferent inputs, neuronal pathways are activated that influence energy flux and nutrient metabolism in the body and ensure reproductive competency. Growing evidence supports the hypothesis that reduced central nervous system insulin signaling from either defective secretion or action contributes to the pathogenesis of common metabolic disorders, including diabetes and obesity, and may therefore help to explain the close association between these two disorders. These considerations implicate insulin action in the brain, an organ previously considered to be insulin independent, as a key determinant of both glucose and energy homeostasis. Diabetes 54: 1264 -1276, 2005 A n important function of the central nervous system (CNS) is to ensure a steady supply of energy substrate to maintain the body economy and prepare for reproduction. To accomplish this task, widely divergent afferent signals must be integrated and transduced into homeostatic adjustments of food intake, energy expenditure, and nutrient metabolism.This perspectives article focuses on recent progress in our understanding of neuronal insulin action and the critical role it plays in energy homeostasis. Based on this information, we hypothesize that the close association between diabetes and obesity in humans arises, at least in part, as a consequence of deficient insulin signaling in both the CNS and peripheral tissues.Studies conducted Ͼ50 years ago first implicated the ventral hypothalamus as a key brain area in energy homeostasis, and an explosion of new information has both confirmed this early impression and illuminated many of the critical mechanisms involved. Among the key findings is evidence that insulin functions not only as a peripheral regulator of nutrient storage and release of circulating substrates but as a key afferent signal to the CNS for the control of energy balance. Indeed, neuronal insulin signaling is known to be important for the control of fat storage in animals as primitive as C. elegans and Drosophilia melanogaster, and the cellular signaling systems mediating these effects bear remarkable homology to those described in mammals. New data have also shown that neuronal insulin signaling is a determinant of lifespan and reproductive function in these organisms, further broadening the importance of this system to diverse areas of physiology and biomedicine.While we note growing evidence implicating insulin action in the control of cognition and neuronal function in cortical and hippocampal areas important to memory formation and information processing, this is not the focus of this article. However, we p...

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Leptin inhibits rat hippocampal neurons via activation of large conductance calcium-activated K+ channels

Cited by 80 publications

References 10 publications

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

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

Alteration of hypothalamic cellular dynamics in obesity

Insulin Signaling in the Central Nervous System

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