Memory and synaptic plasticity are impaired by dysregulated hippocampal O-GlcNAcylation

O-GlcNAcylated proteins are abundant in the brain and are associated with neuronal functions and neurodegenerative diseases. Although several studies have reported the effects of aberrant regulation of O-GlcNAcylation on brain function, the roles of O-GlcNAcylation in synaptic function remain unclear. To understand the effect of aberrant O-GlcNAcylation on the brain, we used Oga+/- mice which have an increased level of O-GlcNAcylation, and found that Oga+/- mice exhibited impaired spatial learning and memory. Consistent with this result, Oga+/- mice showed a defect in hippocampal synaptic plasticity. Oga heterozygosity causes impairment of both long-term potentiation and long-term depression due to dysregulation of AMPA receptor phosphorylation. These results demonstrate a role for hyper-O-GlcNAcylation in learning and memory.ope

Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence

About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer’s disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches

One‐Year Landmark Analysis of the Effect of Beta‐Blocker Dose on Survival After Acute Myocardial Infarction

Background Although beta‐blockers are recommended following myocardial infarction (MI), the benefits of long‐term treatment have not been established. The study's aim was to evaluate beta‐blocker efficacy by dose in 1‐year post‐MI survivors. Methods and Results The OBTAIN (Outcomes of Beta‐Blocker Therapy After Myocardial Infarction) registry included 7057 patients with acute MI, with 6077 one‐year survivors. For this landmark analysis, beta‐blocker dose status was available in 3004 patients and analyzed by use (binary) and dose at 1 year after MI. Doses were classified as no beta‐blocker and >0% to 12.5%, >12.5% to 25%, >25% to 50%, and >50% of target doses used in randomized clinical trials. Age was 63 to 64 years, and approximately two thirds were men. Median follow‐up duration was 1.05 years (interquartile range, 0.98–1.22). When analyzed dichotomously, beta‐blocker therapy was not associated with improved survival. When analyzed by dose, propensity score analysis showed significantly increased mortality in the no–beta‐blocker group (hazard ratio,1.997; 95% CI, 1.118–3.568; P 0% to 12.5% group (hazard ratio, 1.817; 95% CI, 1.094–3.016; P 25% to 50% group (hazard ratio, 1.764; 95% CI, 1.105–2.815; P 12.5% to 25% dose group. The mortality in the full‐dose group was not significantly higher (hazard ratio, 1.196; 95% CI, 0.687–2.083). In subgroup analyses, only history of congestive heart failure demonstrated significant interaction with beta‐blocker effects on survival. Conclusions This analysis suggests that patients treated with >12.5% to 25% of the target dose used in prior randomized clinical trials beyond 1 year after MI may have enhanced survival compared with no beta‐blocker and other beta‐blocker doses. A new paradigm for post‐MI beta‐blocker therapy is needed that addresses which patients should be treated, for how long, and at what dose