Microtubule disruption, not calpain-dependent loss of MAP2, contributes to enduring NMDA-induced dendritic dysfunction in acute hippocampal slices.

Brief exposure to excitotoxic agonists can result in substantial loss of the microtubule-associated protein MAP2 from neuronal dendrites, and accumulation in somata. A possible mechanism underling MAP2 loss is the activation of the calcium-dependent protease calpain by excessive dendritic Ca2+-loading. The present study examined mechanisms of MAP2 redistribution and loss of synaptic efficacy in the CA1 region of acutely prepared hippocampal slices. Brief NMDA exposure resulted in persistent and profound inhibition of postsynaptic potentials, and loss of MAP2 from dendritic compartments. When Ca2+ was removed during NMDA exposure, synaptic potentials recovered significantly during NMDA washout, and MAP2 loss was reduced. Calpain inhibition with MDL 28,170 (20 microM) did not prevent the loss of synaptic potentials, nor did it attenuate the initial aggregation of MAP2 into irregular dendritic swellings. However MDL 28,170 did reduce subsequent MAP2 loss from abnormal dendritic aggregates. Pre-exposure of slices to taxol (100 nM) effectively prevented microtubule depolymerization following NMDA exposure, as well as MAP2 disorganization and loss from apical dendrites. Slices treated with taxol also exhibited substantial recovery of synaptic potentials after transient NMDA stimulus. These results demonstrate a close correspondence between the maintained localization of MAP2 in apical dendrites and the recovery of postsynaptic potentials following transient NMDA exposure. In addition, it appears that rather than underlying the initial disruption of microtubule structure via MAP2 proteolysis, calpain activity instead may contribute to the degradation of irregularly aggregated MAP2 observed following microtubule depolymerization.