Consistent with the results of experiments put forward in this paper, perforin heterozygosity predisposed these animals to undergo vascular permeability shown by FITC-albumin leakage and functional impairment on the rotarod when compared to perforin deficient littermate controls. This experiment demonstrates that only one perforin allele is necessary to induce this syndrome and minimizes the likelihood of other contributing alleles on the C57BL/ 6 Prf12/2 mouse background that may have resulted through genetic drift or incomplete crossing from the 129 svlm mouse background. An alternative model is that CD8 T cells destroy vascular CECs directly through direct perforin-mediated killing. Studies in murine cerebral malaria have found that perforin deficient mice are resistant to CEC damage, as assessed by active caspase-3 staining. The authors demonstrate that caspase-3 activation in CECs occurred simultaneously with edema and petechial hemorrhage and that this process was perforin dependent. We also observed caspase-3 activation in microvessel isolates at 24 hours post VP2121�C130 peptide administration when the C57BL/6 mice were moribund. However, the onset of FITCalbumin leakage occurs much earlier, peaking at 12 hours post administration of VP2121�C130 peptide which is considerably earlier than observable active caspase-3 in microvessel isolates. Our kinetic analysis therefore does not AbMole BioScience readily support a mechanism in which caspase-3 mediated apoptosis is the initiator of CNS vascular permeability. Furthermore, while we observed decreases in microvessel occludin following VP2121�C130 peptide administration, Claudin-5 levels dramatically Masitinib increased. These data suggest that CECs remained viable and capable of protein expression while peak permeability was occurring. Our analysis of tight junction proteins and active caspase-3 protein in microvessel isolates supports a model in which perforin mediates vascular permeability through a mechanism that is not directly apoptotic to the vasculature or utilizes a pathway that does not involve caspase-3 activation. A non-apoptotic role for perforin has been previously implied in studies demonstrating the capacity of CD8 T cells to control Herpes simplex virus replication in ganglionic neurons through a mechanism that does not result in apoptosis. Extending this observation to other CNS cell types enables one to hypothesize that perforin could potentially deliver inflammatory factors to CNS cell types, including cellular components of the neurovascular unit, without initiating apoptosis. Impulsivity is a multifaceted construct covering various, largely independent, behavioral measures ranging from impulsive actions, e.g. disturbed inhibitory control and response inhibition, to impulsive decisions, e.g. delay aversion.