In addition, targeted deletion of another BH3-only proapoptotic molecule BIM (BCL2-Interacting Mediator of cell death) in the brain did not confer resistance Capmatinib solubility dmso against acute seizures ( Figure S4). Thus, it appears that the seizure-resistance phenotype of BAD mutant mice is neither related to BAD’s apoptotic role nor universally shared among other BCL-2 family members. Changes in the preferential ability to utilize ketone bodies in the absence of BAD and the attendant resistance to acute seizures may derive from local metabolic alterations in the brain and/or from altered metabolism in the liver, which is the body’s main source of ketone body production. Two lines of investigation suggest

that seizure protection in the absence of BAD cannot be explained by systemic alterations in ketone body metabolism. First, we have not observed any differences in the serum levels of ketone bodies in these animals (data not shown). Second, liver-specific knockdown of Bad does not produce seizure protection in mice ( Figure S5), despite fully mimicking the hepatic phenotype of Bad−/− mice (data not shown). These results are especially relevant as liver is the chief source of ketone bodies for systemic supply to other tissues. Our observations suggest that local

metabolic alterations in the brain of Bad−/− animals, rather than systemic changes in ketone body metabolism, most likely contribute to seizure protection in the absence of BAD. Seizures produced by kainic acid, as for several other convulsant treatments in rodents, appear first as hypoactivity and focal “limbic this website seizures” involving automatisms, facial and forelimb clonus, and rearing; these seizures can progress to generalized tonic-clonic seizures and death (Velíšková, 2005). The former are attributed to forebrain or limbic activity, whereas the generalized seizures are thought to be mediated by brainstem or midbrain reticular systems (Browning, 1994). In several rodent seizure models

that follow this pattern, clinically useful anticonvulsants, such as phenytoin (Browning et al., 1990), levetiracetam (Klitgaard et al., 1998), and topiramate (Haugvicová et al., 2000), have little effect on the focal seizures but disrupt progression to generalized motor seizures. A similar protection against generalized seizures in the intraperitoneal (i.p.) kainate the model was seen in the behavioral experiments on mice with alteration of BAD. Bad−/− mice or BadS155A knockin mice rarely exhibited generalized motor seizures (and when they occurred they were very brief), whereas most control animals had severe generalized seizures, and many control animals died during status epilepticus ( Figures 3 and S2). In addition to noting this marked difference in behavioral seizure response, we performed video-electroencephalographic (EEG) analysis of the behavioral and electrographic seizures in cohorts of wild-type and Bad−/− mice subjected to i.p. kainate injection ( Figure 4).