Reelin Modulates NMDA Receptor Activity in Cortical Neurons

• Published in: The Journal of neuroscience Vol. 25; no. 36; pp. 8209 - 8216
• Main Authors: Chen, Ying, Beffert, Uwe, Ertunc, Mert, Tang, Tie-Shan, Kavalali, Ege T, Bezprozvanny, Ilya, Herz, Joachim
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 07.09.2005; Society for Neuroscience
• Subjects: 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology; Animals; Cell Adhesion Molecules, Neuronal - physiology; Cerebral Cortex - drug effects; Cerebral Cortex - physiology; Development/Plasticity/Repair; Excitatory Amino Acid Antagonists - pharmacology; Extracellular Matrix Proteins - physiology; Female; Mice; Nerve Tissue Proteins - physiology; Neurons - physiology; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - physiology; Serine Endopeptidases - physiology; Signal Transduction - physiology; Synaptic Transmission - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1951-05.2005

Reelin, a large protein that regulates neuronal migration during embryonic development, activates a conserved signaling pathway that requires its receptors, very low-density lipoprotein receptor and apolipoprotein E receptor 2, the cytoplasmic adaptor protein Disabled-1 (Dab1), and Src family kinases (SFK). Reelin also markedly enhances long-term potentiation in the adult hippocampus, suggesting that this developmental signaling pathway can physiologically modulate learning and behavior. Here, we show that Reelin can regulate NMDA-type glutamate receptor activity through a mechanism that requires SFKs and Dab1. Reelin mediates tyrosine phosphorylation of and potentiates calcium influx through NMDA receptors in primary wild-type cortical neurons but not in Dab1 knock-out neurons or in cells in which Reelin binding to its receptors is blocked by a receptor antagonist. Inhibition of SFK abolishes Reelin-induced and glutamate-dependent enhancement of calcium influx. We also show that Reelin-induced augmentation of Ca2+ entry through NMDA receptors increases phosphorylation and nuclear translocation of the transcription factor cAMP-response element binding protein. Thus, Reelin may physiologically modulate learning and memory by modulating NMDA receptor functions.