👤 Joshua D Milner

Major depressive disorder is associated with deficits in hippocampal synaptic plasticity that depend on brain-derived neurotrophic factor (BDNF) release from both axonal and dendritic compartments. Antidepressant efficacy requires enhanced BDNF signaling, thought to be mediated by drug-induced BDNF release from postsynaptic dendritic spines. Here, we show that fast-acting antidepressants rapidly trigger BDNF secretion from presynaptic terminals in hippocampal area CA3. At antidepressant-relevant concentrations, ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) induced BDNF release within minutes from mossy fiber terminals of dentate granule neurons in rat hippocampal cultures, with no detectable secretion from dendritic spines. This antidepressant-evoked BDNF release required presynaptic NMDA receptors (preNMDARs). Conditional genetic deletion of preNMDARs from granule neurons abolished ketamine- and HNK-induced BDNF exocytosis in acute mouse hippocampal slices, establishing a presynaptic receptor mechanism for antidepressant-induced neurotrophin release. In CA3 pyramidal neurons that receive mossy fiber input, both compounds induced rapid remodeling of dendritic spines, resulting in increased spine density. Together, these findings identify presynaptic terminals as a previously unrecognized source of antidepressant-evoked BDNF release and establish a new cellular mechanism for the rapid synaptic effects of fast-acting antidepressants. Show less

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death. Systemic autoimmune and inflammatory diseases are associated with increased ASCVD risk, severity, and mortality. The inflammatory cytokine interleukin 9 (IL-9) has been linked to murine atherogenesis, raising fundamental questions about the populations in which and the mechanisms by which IL-9 drives ASCVD. Circulating T helper subsets and coronary computed tomography angiography data were analysed in patients with psoriasis. Murine models of psoriatic atherogenesis (imiquimod-ApoE Here, we found that expansion of IL-9-producing T helper cells (Th9) was significantly associated with high-risk radiographic ASCVD in patients with the autoimmune disease psoriasis. Th9 cells were poised to migrate to coronary vessels and were identified in human atherosclerotic plaque from individuals with psoriasis. In vivo, murine inflammatory atherogenesis was prevented by IL-9 blockade and by IL-9 receptor (IL-9R) deletion in endothelial cells. In human arterial endothelial cells, IL-9R/STAT3 signalling promoted endothelial dysfunction via diverse mechanisms including adhesion, activation, angiogenesis, and release of leukocyte chemoattractants. These findings suggest the Th9 Show less

The BRCA2 gene is mutated in familial breast and ovarian cancer, and its product is implicated in DNA repair and transcriptional regulation. Here we identify a protein, EMSY, which binds BRCA2 within a region (exon 3) deleted in cancer. EMSY is capable of silencing the activation potential of BRCA2 exon 3, associates with chromatin regulators HP1beta and BS69, and localizes to sites of repair following DNA damage. EMSY maps to chromosome 11q13.5, a region known to be involved in breast and ovarian cancer. We show that the EMSY gene is amplified almost exclusively in sporadic breast cancer (13%) and higher-grade ovarian cancer (17%). In addition, EMSY amplification is associated with worse survival, particularly in node-negative breast cancer, suggesting that it may be of prognostic value. The remarkable clinical overlap between sporadic EMSY amplification and familial BRCA2 deletion implicates a BRCA2 pathway in sporadic breast and ovarian cancer. Show less