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Repeated activation of N-Methyl-D-aspartate receptors (NMDARs) causes a Ca2+-dependent reduction in NMDAR-mediated current in dopamine (DA) neurons of the substantia nigra pars compacta (SNc) in one week old rats; however, a Ca2+-dependent regulatory protein has not been identified. The role of the Ca2+-dependent cysteine protease, calpain, in mediating NMDAR current rundown was investigated. In brain slices from rats aged postnatal day 7–9 (‘P7’), bath application of either of the membrane permeable calpain inhibitors, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN, 20 μM) or MDL-28170 (30 μM) significantly reduced whole-cell NMDAR current rundown. To investigate the role of the calpain-2 isoform, the membrane permeable calpain-2 inhibitor, Z-Leu-Abu-CONH-CH2-C6H3 (3, 5-(OMe)2 (C2I, 200 nM), was applied; C2I application significantly reduced whole cell NMDAR current rundown. Interestingly, ALLN but not C2I significantly reduced rundown of NMDA-EPSCs. These results suggest the calpain-2 isoform mediates Ca2+-dependent regulation of extrasynaptic NMDAR current in the first postnatal week, while calpain-1 might mediate rundown of synaptic NMDAR currents. One week later in postnatal development, at P12-P16 (‘P14’), there was significantly less rundown in SNc-DA neurons, and no significant effect on rundown of either Ca2+ chelation or treatment with the calpain inhibitor, ALLN, suggesting that the rundown observed in SNc-DA neurons from two week-old rats might be Ca2+-independent. In conclusion, Ca2+-dependent rundown of extrasynaptic NMDAR currents in SNc DA neurons involves calpain-2 activation, but Ca2+- and calpain-2-dependent NMDAR current rundown is developmentally regulated.Ca2+-dependent rundown of NMDAR current occurs in P7 rat SNc-DA neurons.Inhibitors of the Ca2+-dependent protease, calpain, reduce NMDAR current rundown.Calpain-2 inhibition reduces whole-cell but not synaptic NMDAR current rundown.Ca2+- and calpain-dependent NMDAR current rundown is developmentally regulated.Ca2+- and calpain-dependent NMDAR current rundown may serve a neuroprotective role.