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Neurotransmitter activation of G protein-coupled receptors differentially modulate neural information transfer and activity. A recent study by Tian and colleagues have identified that activation of two ion channels, Transient Receptor Potential Channel 4 (TRPC4) and G protein-coupled inward rectifier K+ (GIRK) modulate action potential firing upon co-activation G i/o and G q by co-released neurotransmitters. Here, we discuss these results suggesting a nonlinear interaction of coincidental G i/o and G q/11 activation that yields discernible neuronal activity patterns during neurotransmission., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Several proteins containing C2 domains have been identified as Ca 2+ sensors for neurotransmitter release. In several cases, multiple C2 domain containing proteins function together to sustain evoked synchronous and asynchronous release as well as Ca 2+ -dependent forms of spontaneous release. Most recent publication by Li and colleagues have identified a novel Ca 2+ sensor at the C. elegans neuromuscular junction [8] that complements the fast Ca 2+ sensor synaptotagmin-1 in mediating a slower form of evoked release. Here, we discuss these results as well as earlier work suggesting an evolutionarily conserved diversity of Ca 2+ sensors mediating distinct forms of neurotransmitter release., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Synaptic transmission relies on rapid calcium (Ca 2+ ) influx into presynaptic terminal via voltage-gated Ca 2+ channels. However, smooth ER is present in presynaptic terminals and accumulating evidence indicate that ER Ca 2+ signaling may play a modulatory role in synaptic transmission. Most recent publication by Lindhout and colleagues (EMBO J, 38 (2019) e101345) suggested that the fragmentation state of the ER affects synaptic vesicle release. Here we discuss these results as well as several key publications that addressed a connection between ER Ca 2+ signaling and synaptic transmission., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Major depressive disorder is a devastating mental disorder. Current antidepressant medications can be effective for some patients with depression; however, these drugs exert mood-elevating effects only after prolonged administration, and a sizable fraction of the patient population fails to respond to treatment. There is an urgent need for faster-acting antidepressants with reliable treatment outcomes and sustained efficacy for individuals with depression, in particular those contemplating suicide. Recent clinical studies report that ketamine, an ionotropic glutamatergic N-methyl-D-aspartate (NMDA) receptor blocker, shows fast-acting antidepressant action, thus bringing fresh perspective into preclinical studies investigating novel antidepressant targets and treatments. Our recent studies show that the effects of ketamine are dependent on brain-derived neurotrophic factor (BDNF) and subsequent activation of the high-affinity BDNF receptor, TrkB. Our findings also suggest that the fast-acting antidepressant effects of ketamine require rapid protein translation, but not transcription, resulting in robust increases in dendritic BDNF protein levels that are important for the behavioral effect. These findings also uncover eukaryotic elongation factor 2 kinase (eEF2K), a Ca²⁺/calmodulin dependent serine/threonine kinase that phosphorylates eEF2 and regulates the elongation step of protein translation, as a major molecular substrate mediating the rapid antidepressant effect of ketamine. Our results show that ketamine-mediated suppression of resting NMDA receptor activity leads to inhibition of eEF2 kinase and subsequent dephosphorylation of eEF2 and augmentation of BDNF synthesis. This article outlines our recent studies on the synaptic mechanisms that underlie ketamine action, in particular the properties of eEF2K as a potential antidepressant target., (Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Subtle alterations in synaptic function contribute to the pathophysiology associated with several neuropsychiatric diseases. Modifications in synaptic vesicle trafficking can cause frequency-dependent changes in neurotransmission, alter information coding in neural circuits, and affect long-term plasticity. Rett syndrome, a neurodevelopmental disorder that arises from mutations in the methyl-CpG-binding protein-2 (MeCP2) gene, is a salient example for such a disease state in which synaptic transmission-in particular, spontaneous neurotransmission and short-term synaptic plasticity, have been altered. MeCP2 is widely believed to be a transcriptional repressor that silences methylated genes. Recent studies have identified synaptic deficits associated with the loss of MeCP2 in several brain regions, including the hippocampus. These findings suggest a synaptic basis for neurological symptoms associated with Rett syndrome and suggest an important role for transcriptional repression in the regulation of neurotransmission. These studies also highlight the importance of histone deacetylation and DNA methylation, two key epigenetic mechanisms in controlling synaptic function. These mechanisms are essential for chromatin remodeling in neurons as well as for repression of gene activation by MeCP2 and related methyl-binding proteins. Future work focusing on the regulation of DNA methylation and histone deacetylation by synaptic activity and how these epigenetic alterations affect neurotransmission will be critical to elucidate the mechanisms underlying Rett syndrome. In addition, this work will also help delineate a key pathway that regulates properties of neurotransmission in the central nervous system that may underlie additional neuropsychiatric disorders.