Rapid-acting antidepressants and the regulation of TrkB neurotrophic signalling-Insights from ketamine, nitrous oxide, seizures and anaesthesia

Increased glutamatergic neurotransmission and synaptic plasticity in the prefrontal cortex have been associated with the rapid antidepressant effects of ketamine. Activation of BDNF (brain-derived neurotrophic factor) receptor TrkB is considered a key molecular event for antidepressant-induced functional and structural synaptic plasticity. Several mechanisms have been proposed to underlie ketamine's effects on TrkB, but much remains unclear. Notably, preliminary studies suggest that besides ketamine, nitrous oxide (N2O) can rapidly alleviate depressive symptoms. We have shown nitrous oxide to evoke TrkB signalling preferentially after the acute pharmacological effects have dissipated (ie after receptor disengagement), when slow delta frequency electroencephalogram (EEG) activity is up-regulated. Our findings also demonstrate that various anaesthetics and sedatives activate TrkB signalling, further highlighting the complex mechanisms underlying TrkB activation. We hypothesize that rapid-acting antidepressants share the ability to regulate TrkB signalling during homeostatically evoked slow-wave activity and that this mechanism is important for sustained antidepressant effects. Our observations urge the examination of rapid and sustained antidepressant effects beyond conventional receptor pharmacology by focusing on brain physiology and temporally distributed signalling patterns spanning both wake and sleep. Potential implications of this approach for the improvement of current therapies and discovery of novel antidepressants are discussed.Peer reviewe

STIM2 regulates PKA-dependent phosphorylation and trafficking of AMPARs

STIMs (STIM1 and STIM2 in mammals) are transmembrane proteins that reside in the endoplasmic reticulum (ER) and regulate store-operated Ca2+ entry (SOCE). The function of STIMs in the brain is only beginning to be explored, and the relevance of SOCE in nerve cells is being debated. Here we identify STIM2 as a central organizer of excitatory synapses. STIM2, but not its paralogue STIM1, influences the formation of dendritic spines and shapes basal synaptic transmission in excitatory neurons. We further demonstrate that STIM2 is essential for cAMP/PKA-dependent phosphorylation of the AMPA receptor (AMPAR) subunit GluA1. cAMP triggers rapid migration of STIM2 to ER–plasma membrane (PM) contact sites, enhances recruitment of GluA1 to these ER-PM junctions, and promotes localization of STIM2 in dendritic spines. Both biochemical and imaging data suggest that STIM2 regulates GluA1 phosphorylation by coupling PKA to the AMPAR in a SOCE-independent manner. Consistent with a central role of STIM2 in regulating AMPAR phosphorylation, STIM2 promotes cAMP-dependent surface delivery of GluA1 through combined effects on exocytosis and endocytosis. Collectively our results point to a unique mechanism of synaptic plasticity driven by dynamic assembly of a STIM2 signaling complex at ER-PM contact sites

Alternative bioherbicide based on Trichoderma koningiopsis: Enzymatic characterization and its effect on cucumber plants and soil organism

none14siThe work aimed to produce and characterize a biocompound based on Trichoderma koningiopsis; to evaluate the phytotoxic and morphological effects on cucumber plants (Cucumis sativus) model, and to study the ecotoxicity of the bioproduct in earthworms. The biocompound was produced by submerged fermentation to obtain the crude extract (ECd), filtered solution with filter paper (FilP), and gauze (FilG). From the ECd, the activity of the enzyme's amylases, cellulases, lipases, and total peroxidases was determined, with three replicates. Among the evaluated enzymes, a high concentration of total peroxidases (44 U mL−1) was observed. The ECd, FilP, and FilG biocompound preparations were applied to cucumber plants, isolated, and combined with the commercial herbicide based on potassium glyphosate. The FilG treatment caused the control of up to 80% of the cucumber plants 15 days after application. However, when FilG was combined with the herbicide glyphosate potassium, there was total depigmentation of 95% of the leaves and mortality of more than 90% of the cucumber plants. In evaluating ecotoxicity with earthworms (Eisenia andrei), there was no mortality when the organisms were exposed to the biocompound preparations; however, 68% rejected the biocompound associated with commercial herbicide was observed. In this way, T. koningiopsis biocompound demonstrated the potential action as a bioherbicide, with relevant data for the agricultural sector, to search for alternative methods to reduce costs and promote food and environmental security.noneUlrich A.; Lerin L.A.; Camargo A.F.; Scapini T.; Diering N.L.; Bonafin F.; Gasparetto I.G.; Confortin T.C.; Sansonovicz P.F.; Fabian R.L.; Reichert Junior F.W.; Treichel H.; Muller C.; Mossi A.J.Ulrich, A.; Lerin, L. A.; Camargo, A. F.; Scapini, T.; Diering, N. L.; Bonafin, F.; Gasparetto, I. G.; Confortin, T. C.; Sansonovicz, P. F.; Fabian, R. L.; Reichert Junior, F. W.; Treichel, H.; Muller, C.; Mossi, A. J

Homeostatic synaptic scaling: molecular regulators of synaptic AMPA-type glutamate receptors

The ability of neurons and circuits to maintain their excitability and activity levels within the appropriate dynamic range by homeostatic mechanisms is fundamental for brain function. Neuronal hyperactivity, for instance, could cause seizures.  One such homeostatic process is synaptic scaling, also known as synaptic homeostasis. It involves a negative feedback process by which neurons adjust (scale) their postsynaptic strength over their whole synapse population to compensate for increased or decreased overall input thereby preventing neuronal hyper- or hypoactivity that could otherwise result in neuronal network dysfunction. While synaptic scaling is well-established and critical, our understanding of the underlying molecular mechanisms is still in its infancy. Homeostatic adaptation of synaptic strength is achieved through upregulation (upscaling) or downregulation (downscaling) of the functional availability of AMPA-type glutamate receptors (AMPARs) at postsynaptic sites.  Understanding how synaptic AMPARs are modulated in response to alterations in overall neuronal activity is essential to gain valuable insights into how neuronal networks adapt to changes in their environment, as well as the genesis of an array of neurological disorders. Here we discuss the key molecular mechanisms that have been implicated in tuning the synaptic abundance of postsynaptic AMPARs in order to maintain synaptic homeostasis