Leptin down-regulates KCC2 activity and controls chloride homeostasis in the neonatal rat hippocampus
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SHORT REPORT
Leptin down‑regulates KCC2 activity and controls chloride homeostasis in the neonatal rat hippocampus Camille Dumon1,3, Yasmine Belaidouni1, Diabe Diabira1, Suzanne M. Appleyard2, Gary A. Wayman2 and Jean‑Luc Gaiarsa1*
Abstract The canonical physiological role of leptin is to regulate hunger and satiety acting on specific hypothalamic nuclei. Beyond this key metabolic function; leptin also regulates many aspects of development and functioning of neuronal hippocampal networks throughout life. Here we show that leptin controls chloride homeostasis in the developing rat hippocampus in vitro. The effect of leptin relies on the down-regulation of the potassium/chloride extruder KCC2 activity and is present during a restricted period of postnatal development. This study confirms and extends the role of leptin in the ontogenesis of functional GABAergic inhibition and helps understanding how abnormal levels of leptin may contribute to neurological disorders. Keywords: GABA, KCC2, Chloride homeostasis, Hippocampus, Rat, Leptin, Maternal obesity Introduction Leptin, the product of the obese (ob) gene, is a circulating hormone secreted mainly from the white adipocytes and transported across the blood brain barrier to the hypothalamus to suppress appetite and enhance metabolism in adult [1]. The hypothalamus is not the only central nervous system target for leptin, as a high density of leptin receptors are expressed in other brain areas including the hippocampus where leptin receptors regulate many aspects of synaptic plasticity and cognitive function [2, 3]. A large body of evidence indicates that leptin also acts as an important neurodevelopmental factor during the perinatal period [4–6]. Thus, while plasma leptin levels reflect adiposity in adult rodents, leptin levels surge during the two first postnatal weeks of life regardless of the animal’s weight or body fat mass [1]. A similar restricted *Correspondence: jean‑[email protected] 1 Aix-Marseille Univ UMR 1249, INSERM (Institut National de La Santé et de La Recherche Médicale) Unité 1249, INMED (Institut de Neurobiologie de La Méditerranée), Parc Scientifique de Luminy, Marseille, France Full list of author information is available at the end of the article
surge of plasma levels is observed during the last trimester of gestation in human [7]. Along with the leptin surge, leptin receptors are expressed and functional in several brain regions at embryonic and postnatal stages and activation of these receptors promote neuronal networks development [8–14]. Due to the many important physiological and developmental functions of leptin, dysregulation in its availability or signaling has been proposed as causal factors for the occurrence of neurological disorders [15–23]. Abnormalities in GABAergic synaptic transmission are strongly associated with neurological disorders [24, 25]. Therefore, understanding whether and how leptin controls the development and efficacy of the GABAergic transmission is warranted. Leptin deficient (ob/ob) mice exhibi
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