Leptin enhances NR2B-mediated N-methyl-D-aspartate responses via a mitogen-activated protein kinase-dependent process in cerebellar granule cells.
It is well documented that the hormone leptin regulates energy balance via its actions in the hypothalamus. However, evidence is accumulating that leptin plays a key role in numerous CNS functions. Indeed, leptin receptors are expressed in many extrahypothalamic brain regions, with high levels found in the hippocampus and cerebellum. In the hippocampus leptin has been shown to facilitate N-methyl-D-aspartate receptor function and modulate synaptic plasticity. A role for leptin in cerebellar function is also indicated as leptin-deficient rodents display reduced mobility that is unrelated to obesity. Here we show that leptin receptor immunolabeling can be detected in cultured cerebellar granule cells, being expressed at the somatic plasma membrane and also concentrated at synapses. Furthermore, leptin facilitated NR2B N-methyl-D-aspartate receptor-mediated Ca2+ influx in cerebellar granule cells via a mitogen-activated protein kinase-dependent pathway. These findings provide the first direct evidence for a cellular action of leptin in cerebellar neurons. In addition, given that N-methyl-D-aspartate receptor activity in the cerebellum is crucial for normal locomotor function, these data also have important implications for the potential role of leptin in the control of movement.
Irving
A J
AJ
Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.
Wallace
L
L
Durakoglugil
D
D
Harvey
J
J
D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009068:Movement / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism; D054411:Receptors, Leptin; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D020738:Leptin; C121001:NR2B NMDA receptor; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid