Proteolytically generated fragments of the microfilament anchoring protein brain spectrin were found to accumulate in brindled mouse brain. Proteolysis was most extensive in brain regions possessing high concentrations of N-methyl-D-aspartate (NMDA) receptors (e.g. cortex, striatum, hippocampus). The brindle mutation affects copper homeostasis and thus a variety of copper-dependent enzymes needed in intermediary metabolism. The altered mitochondria of these mice are suggested to less efficiently buffer NMDA receptor-gated calcium fluxes, thus promoting activation of calcium-activated proteases and subsequent degradation of the spectrin meshwork.