Summary NMDA receptor-dependent synaptic modifications, such as long-term potentiation (LTP) and long-term depression (LTD), are essential for brain development and function. LTD occurs mainly by the removal of AMPA receptors from the postsynaptic membrane, but the underlying molecular mechanisms remain unclear. Here we show that activation of caspase-3 via mitochondria is required for LTD and AMPA receptor internalization in hippocampal neurons. LTD and AMPA receptor internalization are blocked by peptide inhibitors of caspase-3 and -9. In hippocampal slices from caspase-3 knockout mice, LTD is abolished whereas LTP remains normal. LTD is also prevented by overexpression of the anti-apoptotic proteins XIAP or Bcl-xL, and by a mutant Akt1 protein that is resistant to caspase-3 proteolysis. NMDA receptor stimulation that induces LTD transiently activates caspase-3 in dendrites, without causing cell death. These data indicate an unexpected causal link between the molecular mechanisms of apoptosis and LTD.

Importance The prevalence of obesity and outcomes of bariatric surgery are well established. However, analyses of the surgery impact have not been updated and comprehensively investigated since 2003. Objective Up-to-date, comprehensive data and appropriate meta-analytic techniques were used to examine effectiveness and risks of bariatric surgery. Data Sources Literature searches of Medline, Embase, Scopus, Current Contents, Cochrane Library, and Clinicaltrials.gov between 2003 and 2012 were performed. Study Selection Exclusion criteria included publication of abstracts only, case reports, letters, comments, or reviews; animal studies; languages other than English; duplicate studies; no surgical intervention; and no population of interest. Inclusion criteria were at least one outcome of interest resulting from the studied surgery was reported – comorbidities, mortality, complications, reoperations, or weight loss. Of the 25,060 initially identified articles, 24,023 studies met the exclusion criteria, and 259 met the inclusion criteria. Data Extraction A review protocol was followed throughout. Three reviewers independently reviewed studies, abstracted data, and resolved disagreements by consensus. Studies were evaluated for quality. Results A total of 164 studies were included (37 randomized controlled trials (RCTs) and 127 observational studies). Analyses included 161,756 patients with mean age 45 years and body mass index (BMI) 46 kg/m2. We conducted random-effects and fixed-effect meta-analyses and meta-regression. In RCTs, ≤30 days mortality rate was 0.08% [95%CI, 0.01%–0.24%]; >30 days mortality rate was 0.31% [95%CI, 0.01%–0.75%]. BMI loss at the post-surgery five years was 12–17 kg/m2. The complication rate was 17% [95%CI, 11%–23%], and the reoperation rate was 7% [95%CI, 3%–12%]. Gastric bypass (GB) was more effective in weight loss but associated with more complications. Adjustable gastric banding (AGB) had lower mortality and complication rates; yet, the reoperation rate was higher and weight loss was less substantial than GB. Sleeve gastrectomy appeared to be more effective in weight loss than AGB and comparable to GB. Conclusions Bariatric surgery provides substantial and sustained effects on weight loss and ameliorates obesity-attributable comorbidities in the majority of bariatric patients, although risks of complication, reoperation, and death exist. Death rates were lower than those reported in previous meta-analyses.

Summary It has recently been found that caspases not only function in apoptosis, but are also crucial for non-apoptotic processes such as NMDA receptor-dependent long-term depression (LTD) of synaptic transmission. It remains unknown, however, how caspases are activated and how neurons escape death in LTD. Here we show that caspase-3 is activated by the BAD-BAX cascade for LTD induction. This cascade is required specifically for NMDA receptor-dependent LTD but not for mGluR-LTD, and its activation is sufficient to induce synaptic depression. In contrast to apoptosis, however, BAD is activated only moderately and transiently and BAX is not translocated to mitochondria, resulting in only modest caspase-3 activation. We further demonstrate that the intensity and duration of caspase-3 activation determin whether it leads to cell death or LTD, thus fine-tuning of caspase-3 activation is critical in distinguishing between these two pathways.