1These authors contributed equally to this work.Abbreviations used: [Ca 2+ ] i, intracellular calcium level; 3-NP, 3-nitropropionic acid; AIF, apoptosis-inducing factor; cyt c, cytochrome c; DHPG, 3,5-dihydroxyphenylglycine; div, days in vitro; HD, Huntington's disease; HSP60, heat-shock protein 60; HtrA2, high temperature requirement protein A2; IMS, intermembrane space; OMM, outer mitochondrial membrane; PCD, programmed cell death; PI, propidium iodide; SIN-1, 3-morpholinosydnonimine; Smac/DIABLO, second mitochondrial activator of caspases/direct inhibitor of apoptosis protein binding protein of low isoelectric point; STS, staurosporine; TUNEL, terminal transferase-mediated deoxyuridine triphosphate-biotin nick end labeling; DY m, mitochondrial transmembrane potential. AbstractGABAergic striatal neurons are compromised in basal ganglia pathologies and we analysed how insult nature determined their patterns of injury and recruitment of the intrinsic mitochondrial pathway during programmed cell death (PCD). Stressors affecting targets implicated in striatal neurodegeneration [3-morpholinylsydnoneimine (SIN-1), 3-nitropropionic acid (3-NP), NMDA, 3,5-dihydroxyphenylglycine (DHPG), and staurosporine (STS)] were compared in cultured GABAergic neurons from murine striatum by analyzing the progression of injury and its correlation with mitochondrial involvement, the redistribution of intermembrane space (IMS) proteins, and patterns of protease activation. Stressors produced PCD exhibiting slow-onset kinetics with time-dependent annexin-V labeling and eventual DNA fragmentation. IMS proteins including cytochrome c were differentially distributed, although stressors except STS produced early redistribution of apoptosis-inducing factor and Omi, suggestive of early recruitment of both caspase-dependent and caspase-independent signaling. In general, Bax mobilization to mitochondria appeared to promote IMS protein redistribution. Caspase 3 activation was prominent after STS, whereas NMDA and SIN-1 produced mainly calpain activation, and 3-NP and DHPG elicited a mixed profile of protease activation. PCD and redistribution of IMS proteins in striatal GABAergic neurons were canonical and insult-dependent, reflecting differential interplay between the caspase cascade and alternate cell death pathways.