N-METHYL-D-ASPARTATE STIMULATES THE DEPHOSPHORYLATION OF THE MICROTUBULE-ASSOCIATED PROTEIN-2 AND POTENTIATES EXCITATORY SYNAPTIC PATHWAYS IN THE RAT HIPPOCAMPUS

We have studied the effect of brief (50-150 s) applications of N-methy l-p-aspartate (10-100 muM) on the phosphorylated state of the microtub ule-associated protein 2 in slices of rat hippocampus. Following a sim ilar experimental protocol we also studied the pattern of excitatory p ostsynaptic potentials intracellularly recorded in CA1 pyramidal cells elicited by stimulation of the Schaffer collateral-commissural pathwa y. N-Methyl-D-aspartate treatment produced a marked and specific depho sphorylation of the cytoskeletal microtubule-associated protein 2, whi ch was not due to enhanced proteolytic activity. Dephosphorylation of the microtubule-associated protein 2 affects mainly the tubulin-bindin g domain of the molecule and seems to be a consequence of the activati on of the Ca2+/calmodulin-dependent phosphatase calcineurin, as it is partially inhibited by calmidazolium but not by okadaic acid. A few mi nutes after N-methyl-D-aspartate treatment we observed a 23 +/- 17% in crease in the amplitude of the monosynaptic excitatory postsynaptic po tential recorded in the cells and the appearance of a large polysynapt ic excitatory postsynaptic potential. Both effects lasted for several tens of minutes. The late polysynaptic potential was not observed when the CA3 and CA1 subfields were surgically separated. Our results indi cate that the N-methyl-D-aspartate receptor activation leads to the de phosphorylation of the microtubule-associated protein 2 via a Ca2+/cal modulin phosphatase, probably calcineurine. This may, in turn, partici pate in the potentiation of synaptic efficacy.