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

Abstract 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.