Abstract
Both proconvulsive and anticonvulsive roles of leptin have been reported, suggesting cell-specific actions of leptin in different models of seizure and epilepsy. The goal of our study was to determine the regulation and function of astrocytic leptin receptors in a mouse model of epilepsy and glutamate-induced cytotoxicity. We show that in pilocarpine-challenged mice develo** epilepsy with recurrent seizures after a latent period of 2 weeks, hippocampal leptin receptor (ObR) immunofluorescence was increased at 6 weeks. This was more pronounced in astrocytes than in neurons. In cultured astrocytes, glutamate increased ObRa and ObRb expression, whereas leptin pretreatment attenuated glial cytotoxicity by excess glutamate, reflected by better preserved adenosine triphosphate production. The protective role of astrocytic leptin signaling is further supported by the higher lethality of the astrocyte-specific leptin receptor knockout mice in the initial phase of seizure production. Thus, leptin signaling in astrocytes plays a protective role against seizure, and the effects are at least partially mediated by attenuation of glutamate toxicity. Astrocytic leptin signaling, therefore, may be a novel therapeutic target.
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Acknowledgments
Funding support was provided by NIH (DK54880 and DK92245 to AJK and NS62291 to WP). The ObR-floxed mice used to generate ALKO mice originated from Dr. Streamson Chua, Jr. (Department of Pediatrics, Albert Einstein Medical College, New York, NY, USA). The ObRa and ObRb plasmids were kindly provided by Dr. Christian Bjorbaek (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA). We thank Dr. Damir Janigro and Dr. Kirsten Stone for the helpful discussions, Dr. Barry Robert for the assistance in initiating seizure recording and video monitoring, and Ms. Yu** Wang for the technical support.
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Jayaram, B., Khan, R.S., Kastin, A.J. et al. Protective Role of Astrocytic Leptin Signaling Against Excitotoxicity. J Mol Neurosci 49, 523–530 (2013). https://doi.org/10.1007/s12031-012-9924-0
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DOI: https://doi.org/10.1007/s12031-012-9924-0