The cell adhesion molecule neuroplastin-65 inhibits hippocampal long-term potentiation via a mitogen-activated protein kinase p38-dependent reduction in surface expression of GluR1-containing glutamate receptors.
Neuroplastin-65 is a brain-specific, synapse-enriched member of the immunoglobulin (Ig) superfamily of cell adhesion molecules. Previous studies highlighted the importance of neuroplastin-65 for long-term potentiation (LTP), but the mechanism was unclear. Here, we show how neuroplastin-65 activation of mitogen-activated protein kinase p38 (p38MAPK) modified synapse strength by altering surface glutamate receptor expression. Organotypic hippocampal slice cultures treated with the complete extracellular fragment of neuroplastin-65 (FcIg1-3) sustained an increase in the phosphorylation of p38MAPK and an inability to induce LTP at hippocampal synapses. The LTP block was reversed by application of the p38MAPK inhibitor SB202190, suggesting that p38MAPK activation occurred downstream of neuroplastin-65 binding and upstream of the loss of LTP. Further investigation revealed that the mechanism underlying neuroplastin-65-dependent prevention of LTP was a p38MAPK-dependent acceleration of the loss of surface-exposed glutamate receptor subunits that was reversed by pretreatment with the p38MAPK inhibitor SB202190. Our results indicate that neuroplastin-65 binding and associated stimulation of p38MAPK activity are upstream of a mechanism to control surface glutamate receptor expression and thereby influence plasticity at excitatory hippocampal synapses.
Empson
Ruth M
RM
School of Biological Sciences, Royal Holloway University of London, Egham, Surrey, UK. R.Empson@rhul.ac.uk
Buckby
Lucy E
LE
Kraus
Michaela
M
Bates
Katharine J
KJ
Crompton
Mark R
MR
Gundelfinger
Eckart D
ED
Beesley
Philip W
PW
D000818:Animals; D001710:Biotin; D015153:Blotting, Western; D004558:Electric Stimulation; D004594:Electrophysiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009924:Organ Culture Techniques; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000096:biosynthesis* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001710:Biotin; D007093:Imidazoles; D007141:Immunoglobulin Fc Fragments; D019950:Mitogen-Activated Protein Kinase 1; D011725:Pyridines; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole