Phenotypes of DJ. 1 knockout mice Five lines of DJ-1 knockout (KO) mice have been generated and characterized. In one of the DJ-1 KO lines, exons 3-5 were replaced with a neomycin (Neo) selectable cassette in C57Bl/6 background (165). Cortical neurons derived from DJ-1 KO embryos show 20% increase in cell death induced by H2O2, compared to that of WT, and this vulnerability can be rescued by overexpression of DJ-1. Mesencephalic dopaminergic neurons (TH+) from DJ-1 KO mice also show 30% decrease in rotenone-induced cell death. However, DJ-1 KO has no influence on the vulnerability caused by non-oxidative insults such as camptothecin, a topoisomerase I inhibitor. DJ-1 KO mice at the age of 8w and 13m display no gross motor behavior under normal conditions. However, locomotor activity was reduced by 50%, compared to DJ-WT mice, when treated with MPTP. Amphetamine-induced hyperlocomotion is reduced in DJ-1 KO mice as well, indicating that DJ-1 KO mice exhibit normal locomotor behavior when unchallenged, but have deficits upon challenges to the dopaminergic system. Loss of DJ-1 also sensitizes SNpc neurons to MPTP-induced apoptosis, assessed by the number of viable TH+ neurons after MPTP treatment (165). Another line of DJ-1 knockout mice were created by homologous recombination, resulting in deletion of exon 2 (114). This line of DJ-1 KO mice was found to share similar phenotypes as dopamine D2 receptor null mice, although D2 receptor mRNA and protein levels are unaltered in DJ-1 knockout mice. The DJ-1 knockout mice have normal numbers of DA neurons in SN at 12m, but the evoked DA overflow in the striatum is reduced, primarily as a result of increased reuptake. Nigral neurons from knockout mice are less sensitive to the inhibitory effects of D2 autoreceptor stimulation as the inhibitory response of nigral neurons and the blockage of action potential by D2 receptor agonist are decreased in neurons from DJ-1 knockout mice. Corticostriatal long-term potentiation is normal in medium spiny neurons of DJ-1 knockout mice (which requires D1 receptor), but long-term depression (LTD) is absent (which requires both D1 and D2 receptor). The LTD deficit is reversed by treatment with D2 but not D1 receptor agonists. Furthermore, DJ-1 knockout mice display hypoactivity in the open field. The findings suggest an essential role for DJ-1 in DA physiology and D2 receptor-mediated functions (114). The third line of DJ-1 knockout mice shows no major phenotypes. They have normal numbers of DA neur...
