👤 Marco J Herold

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

In contemporary research practice, high-intensity interval training (HIIT) has received growing attention compared to other types of endurance training [e.g., moderate-intensity continuous training (MICT)]. This is primarily related to HIIT's ability to induce higher metabolic stress, driving an increased exerkine secretory response (i.e., of specific proteins) compared to MICT. To date, previous reviews on HIIT have primarily focused on single exerkines, while a more comprehensive analysis, as required to gain a more comprehensive understanding of the complex exercise-related physiological processes, is absent. To reduce non-exercise protocol-related outcome heterogeneity, the rigorous inclusion criteria (i.e., exercise intensity in the HIIT adjusted for the target population of healthy, diseased, or older individuals, and not taking any medications) were applied. A total of 39 studies were selected for the systematic review, with fourteen, twenty-two, and three for the acute, chronic, and both acute and chronic effects of HIIT on exerkine concentrations, respectively. Acute HIIT appears to result in greater changes in BDNF and VEGF concentration than the control group performing lower-intensity exercise or no exercise. Metabolically active exerkine, such as adiponectin, mainly fluctuates among overweight and obese participants. This systematic review did not yield any definitive results regarding alterations in IGF-1, irisin, cortisol, and interleukin levels. Tendentially, HIIT is more effective than MICT and non-exercise interventions to induce a greater secretory response of certain exerkines, such as BDNF, VEGF and adiponectin. Evidence regarding exerkine secretion in response to HIIT among older adults remains limited, highlighting the need for further investigation. Identifier CRD420251003743. Show less

Breast cancer is a heterogeneous disease that comprises multiple histological and molecular subtypes. To gain insight into mutations that drive breast tumorigenesis, we describe a pipeline for the identification and validation of tumor suppressor genes. Based on an in vivo genome-wide CRISPR/Cas9 screen in Trp53 Show less