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Nature Sep 2019High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma...
High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron-glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression.
Topics: Animals; Brain; Cell Membrane; Cell Proliferation; Electrical Synapses; Electrophysiological Phenomena; Gap Junctions; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioma; Heterografts; Humans; Mice; Mice, Inbred NOD; Neurons; Optogenetics; Potassium; Synaptic Transmission; Tumor Cells, Cultured
PubMed: 31534222
DOI: 10.1038/s41586-019-1563-y -
Immunity Jan 2022To accommodate the changing needs of the developing brain, microglia must undergo substantial morphological, phenotypic, and functional reprogramming. Here, we examined...
To accommodate the changing needs of the developing brain, microglia must undergo substantial morphological, phenotypic, and functional reprogramming. Here, we examined whether cellular metabolism regulates microglial function during neurodevelopment. Microglial mitochondria bioenergetics correlated with and were functionally coupled to phagocytic activity in the developing brain. Transcriptional profiling of microglia with diverse metabolic profiles revealed an activation signature wherein the interleukin (IL)-33 signaling axis is associated with phagocytic activity. Genetic perturbation of IL-33 or its receptor ST2 led to microglial dystrophy, impaired synaptic function, and behavioral abnormalities. Conditional deletion of Il33 from astrocytes or Il1rl1, encoding ST2, in microglia increased susceptibility to seizures. Mechanistically, IL-33 promoted mitochondrial activity and phagocytosis in an AKT-dependent manner. Mitochondrial metabolism and AKT activity were temporally regulated in vivo. Thus, a microglia-astrocyte circuit mediated by the IL-33-ST2-AKT signaling axis supports microglial metabolic adaptation and phagocytic function during early development, with implications for neurodevelopmental and neuropsychiatric disorders.
Topics: Animals; Behavior, Animal; Disease Susceptibility; Electrical Synapses; Energy Metabolism; Humans; Interleukin-1 Receptor-Like 1 Protein; Interleukin-33; Mice; Mice, Knockout; Microglia; Mitochondria; Neurogenesis; Oncogene Protein v-akt; Phagocytosis; Seizures; Signal Transduction
PubMed: 34982959
DOI: 10.1016/j.immuni.2021.12.001 -
Nature Reviews. Neuroscience May 2012Neuronal activity in the brain gives rise to transmembrane currents that can be measured in the extracellular medium. Although the major contributor of the extracellular... (Review)
Review
Neuronal activity in the brain gives rise to transmembrane currents that can be measured in the extracellular medium. Although the major contributor of the extracellular signal is the synaptic transmembrane current, other sources--including Na(+) and Ca(2+) spikes, ionic fluxes through voltage- and ligand-gated channels, and intrinsic membrane oscillations--can substantially shape the extracellular field. High-density recordings of field activity in animals and subdural grid recordings in humans, combined with recently developed data processing tools and computational modelling, can provide insight into the cooperative behaviour of neurons, their average synaptic input and their spiking output, and can increase our understanding of how these processes contribute to the extracellular signal.
Topics: Animals; Calcium Signaling; Electrical Synapses; Electroencephalography; Evoked Potentials; Extracellular Space; Humans; Ligand-Gated Ion Channels; Magnetoencephalography; Neural Conduction; Neuroglia; Neurons; Synapses; Voltage-Sensitive Dye Imaging
PubMed: 22595786
DOI: 10.1038/nrn3241 -
Current Biology : CB Nov 2014Synapses are specialized asymmetric cell-cell connections permitting the controlled transfer of an electrical or chemical signal between a presynaptic neuronal cell and...
Synapses are specialized asymmetric cell-cell connections permitting the controlled transfer of an electrical or chemical signal between a presynaptic neuronal cell and a postsynaptic target cell (e.g. neuron or muscle). Adequate synapse function is an essential prerequisite of all neuronal processing, including higher cognitive functions, such as learning and memory. At synapses, neurotransmitters (e.g. amino acids, amines, peptides, and acetylcholine) are released from synaptic vesicles into the synaptic cleft in response to action potentials. The Nobel Prize for Physiology and Medicine in 2013 was awarded to James E. Rothman, Randy W. Schekman and Thomas C. Südhof "for their discoveries of the machinery regulating vesicle traffic, a major transport system in our cells". This included crucial revelations, such as the identification of the core machinery of synaptic vesicle fusion. However, in contrast to the advances concerning the organization of the core functions of the synapse, our current understanding of the processes of synapse formation and maintenance--i.e. 'synaptogenesis'--is still somewhat fragmentary. Here, we will outline the current status and future directions of the field of synaptogenesis, primarily from the perspective of the presynaptic release site.
Topics: Biological Transport; Models, Biological; Synapses; Synaptic Transmission; Synaptic Vesicles
PubMed: 25458214
DOI: 10.1016/j.cub.2014.10.024 -
Developmental Neurobiology May 2017Gap junctions underlie electrical synaptic transmission between neurons. Generally perceived as simple intercellular channels, "electrical synapses" have demonstrated to... (Review)
Review
Gap junctions underlie electrical synaptic transmission between neurons. Generally perceived as simple intercellular channels, "electrical synapses" have demonstrated to be more functionally sophisticated and structurally complex than initially anticipated. Electrical synapses represent an assembly of multiple molecules, consisting of channels, adhesion complexes, scaffolds, regulatory machinery, and trafficking proteins, all required for their proper function and plasticity. Additionally, while electrical synapses are often viewed as strictly symmetric structures, emerging evidence has shown that some components forming electrical synapses can be differentially distributed at each side of the junction. We propose that the molecular complexity and asymmetric distribution of proteins at the electrical synapse provides rich potential for functional diversity. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 562-574, 2017.
Topics: Animals; Electrical Synapses; Gap Junctions
PubMed: 28170151
DOI: 10.1002/dneu.22484 -
Journal of Neurophysiology Oct 2018Neurons communicate with each other via electrical or chemical synaptic connections. The pattern and strength of connections between neurons are critical for generating... (Review)
Review
Neurons communicate with each other via electrical or chemical synaptic connections. The pattern and strength of connections between neurons are critical for generating appropriate output. What mechanisms govern the formation of electrical and/or chemical synapses between two neurons? Recent studies indicate that common molecular players could regulate the formation of both of these classes of synapses. In addition, electrical and chemical synapses can mutually coregulate each other's formation. Electrical activity, generated spontaneously by the nervous system or initiated from sensory experience, plays an important role in this process, leading to the selection of appropriate connections and the elimination of inappropriate ones. In this review, we discuss recent studies that shed light on the formation and developmental interactions of chemical and electrical synapses.
Topics: Animals; Connexins; Electrical Synapses; Humans; Neurogenesis; Synaptic Transmission
PubMed: 30067121
DOI: 10.1152/jn.00398.2018 -
Frontiers in Cellular Neuroscience 2022Electrical synapses are the neurophysiological product of gap junctional pores between neurons that allow bidirectional flow of current between neurons. They are... (Review)
Review
Electrical synapses are the neurophysiological product of gap junctional pores between neurons that allow bidirectional flow of current between neurons. They are expressed throughout the mammalian nervous system, including cortex, hippocampus, thalamus, retina, cerebellum, and inferior olive. Classically, the function of electrical synapses has been associated with synchrony, logically following that continuous conductance provided by gap junctions facilitates the reduction of voltage differences between coupled neurons. Indeed, electrical synapses promote synchrony at many anatomical and frequency ranges across the brain. However, a growing body of literature shows there is greater complexity to the computational function of electrical synapses. The paired membranes that embed electrical synapses act as low-pass filters, and as such, electrical synapses can preferentially transfer spike after hyperpolarizations, effectively providing spike-dependent inhibition. Other functions include driving asynchronous firing, improving signal to noise ratio, aiding in discrimination of dissimilar inputs, or dampening signals by shunting current. The diverse ways by which electrical synapses contribute to neuronal integration merits furthers study. Here we review how functions of electrical synapses vary across circuits and brain regions and depend critically on the context of the neurons and brain circuits involved. Computational modeling of electrical synapses embedded in multi-cellular models and experiments utilizing optical control and measurement of cellular activity will be essential in determining the specific roles performed by electrical synapses in varying contexts.
PubMed: 35755782
DOI: 10.3389/fncel.2022.910015 -
Neuroscience Letters Mar 2019Essentially all animals with nervous systems utilize electrical synapses as a core element of communication. Electrical synapses, formed by gap junctions between... (Review)
Review
Essentially all animals with nervous systems utilize electrical synapses as a core element of communication. Electrical synapses, formed by gap junctions between neurons, provide rapid, bidirectional communication that accomplishes tasks distinct from and complementary to chemical synapses. These include coordination of neuron activity, suppression of voltage noise, establishment of electrical pathways that define circuits, and modulation of high order network behavior. In keeping with the omnipresent demand to alter neural network function in order to respond to environmental cues and perform tasks, electrical synapses exhibit extensive plasticity. In some networks, this plasticity can have dramatic effects that completely remodel circuits or remove the influence of certain cell types from networks. Electrical synaptic plasticity occurs on three distinct time scales, ranging from milliseconds to days, with different mechanisms accounting for each. This essay highlights principles that dictate the properties of electrical coupling within networks and the plasticity of the electrical synapses, drawing examples extensively from retinal networks.
Topics: Animals; Electrical Synapses; Gap Junctions; Humans; Neural Pathways; Neuronal Plasticity; Neurons; Signal Transduction; Synaptic Transmission
PubMed: 28893590
DOI: 10.1016/j.neulet.2017.09.003 -
Frontiers in Immunology 2021
Topics: Animals; Central Nervous System; Electrical Synapses; Humans; Microglia; Neuroimmunomodulation; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 34987527
DOI: 10.3389/fimmu.2021.824866