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 surfaceexposed 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. Keywords: glutamate receptor, hippocampus, long-term potentiation, neuroplastin, mitogen-activated protein kinase p38 , synapse. Cell-cell and cell-extracellular matrix adhesion are critical for the formation of correctly wired neuronal circuits. These adhesive interactions are mediated by a variety of molecules, including the immunoglobulin superfamily (IgSF) members, and also by other families including cadherins, integrins and neurexins (Dityatev and Schachner 2003;Rougon and Hobert 2003).The neuroplastins belong to the IgSF in a subfamily that includes basigin (also called CD147, EMMPRIN), where the defining features are the Ig-like extracellular domains, a short C-terminal, intracellular domain and a transmembrane glutamate residue. The neuroplastins also exist as two alternatively spliced forms of the same gene, neuroplastin-55 (55 kDa) and neuroplastin-65 (65 kDa; Hill et al. 1988;Willmott et al. 1992;Langnaese et al. 1997). Like basigin, neuroplastin-55 contains two common extracellular Ig domains most likely used in heterophilic binding. In contrast, neuroplastin-65 has a third Ig domain that allows homophilic binding; moreover, it is neurone specific and enriched at the Abbreviations used: CA3, cornu ammonis subregion 3 of the hippocampus; ERK, extracellular signal-regulated kinase; fEPSP, field excitatory post-synaptic potential; HFS, high-frequency stimulation; Ig, immunoglobulin; IgSF, immunoglobulin superfamily; LTD, long-term depression; LTP, long-term potentiation; MAP, mitogen-activated protein; p38MAPK, mitogen-activated protein kinase p38; TTX, tetrodotoxin.
