Nuclear calcium signalling in the regulation of brain function
TL;DR: Calcium signals that are induced by synaptic activity and propagate into the nucleus are a major route for synapse-to-nucleus communication and may underlie the aetiologies of various diseases, including neurodegeneration and cognitive dysfunction.
Abstract: Activity-dependent changes in neuronal gene expression require a means of synapse-to-nucleus signalling, and changes in nuclear calcium concentration provide a major route for such communication. Bading discusses how nuclear calcium signals are induced by synaptic activity and describes their role as regulators of gene expression in neuroadaptations.
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TL;DR: Features of brain organization are revealed, including a gene-expression module for synthesizing axonal and presynaptic components, patterns in the co-deployment of voltage-gated ion channels, functional distinctions among the cells of the vasculature and specialization of glutamatergic neurons across cortical regions.
1,110 citations
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...In neurons, the most well-studied state involves the immediate early genes (IEGs), which are transcribed in response to the Ca2+ influx that follows action potentials (Bading, 2013; Hrvatin et al., 2017)....
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...In neurons, the most well-studied state involves the immediate early genes (IEGs), which are transcribed in response to the Ca influx that follows action potentials (Bading, 2013; Hrvatin et al., 2017)....
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TL;DR: The importance of BDNF for future studies aimed at disclosing mechanisms of activation of signaling pathways, neuro- and gliogenesis, as well as synaptic plasticity is highlighted.
Abstract: Brain-derived neurotrophic factor (BDNF) is one of the most widely distributed and extensively studied neurotrophins in the mammalian brain. Among its prominent functions, one can mention control of neuronal and glial development, neuroprotection, and modulation of both short- and long-lasting synaptic interactions, which are critical for cognition and memory. A wide spectrum of processes are controlled by BDNF, and the sometimes contradictory effects of its action can be explained based on its specific pattern of synthesis, comprising several intermediate biologically active isoforms that bind to different types of receptor, triggering several signaling pathways. The functions of BDNF must be discussed in close relation to the stage of brain development, the different cellular components of nervous tissue, as well as the molecular mechanisms of signal transduction activated under physiological and pathological conditions. In this review, we briefly summarize the current state of knowledge regarding the impact of BDNF on regulation of neurophysiological processes. The importance of BDNF for future studies aimed at disclosing mechanisms of activation of signaling pathways, neuro- and gliogenesis, as well as synaptic plasticity is highlighted.
715 citations
Cites background from "Nuclear calcium signalling in the r..."
...The neuroprotective effect can also be achieved due to synaptic NMDAR stimulation and subsequent increase of the nuclear Ca2? influx, which results in activation of CREB and increased expression of genes coding proteins involved in neuroprotection (Bading 2013; Zhao et al. 2017)....
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...The neuroprotective effect can also be achieved due to synaptic NMDAR stimulation and subsequent increase of the nuclear Ca influx, which results in activation of CREB and increased expression of genes coding proteins involved in neuroprotection (Bading 2013; Zhao et al. 2017)....
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TL;DR: The focus of this review is on neuronal Ca2+ signaling and its involvement in synaptic signaling processes, neuronal energy metabolism, and neurotransmission, and the contribution of altered Ca2- signaling in the most important neurological disorders will be considered.
Abstract: Calcium (Ca(2+)) is an universal second messenger that regulates the most important activities of all eukaryotic cells. It is of critical importance to neurons as it participates in the transmission of the depolarizing signal and contributes to synaptic activity. Neurons have thus developed extensive and intricate Ca(2+) signaling pathways to couple the Ca(2+) signal to their biochemical machinery. Ca(2+) influx into neurons occurs through plasma membrane receptors and voltage-dependent ion channels. The release of Ca(2+) from the intracellular stores, such as the endoplasmic reticulum, by intracellular channels also contributes to the elevation of cytosolic Ca(2+). Inside the cell, Ca(2+) is controlled by the buffering action of cytosolic Ca(2+)-binding proteins and by its uptake and release by mitochondria. The uptake of Ca(2+) in the mitochondrial matrix stimulates the citric acid cycle, thus enhancing ATP production and the removal of Ca(2+) from the cytosol by the ATP-driven pumps in the endoplasmic reticulum and the plasma membrane. A Na(+)/Ca(2+) exchanger in the plasma membrane also participates in the control of neuronal Ca(2+). The impaired ability of neurons to maintain an adequate energy level may impact Ca(2+) signaling: this occurs during aging and in neurodegenerative disease processes. The focus of this review is on neuronal Ca(2+) signaling and its involvement in synaptic signaling processes, neuronal energy metabolism, and neurotransmission. The contribution of altered Ca(2+) signaling in the most important neurological disorders will then be considered.
447 citations
Cites background from "Nuclear calcium signalling in the r..."
...These indications are particularly convincing in neurons [124]....
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TL;DR: Evidence both supporting and refuting the localization hypothesis of NMDAR function is reviewed and the role of N MDAR localization in disorders of the nervous system is discussed, particularly in Alzheimer disease and Huntington disease.
422 citations
Cites background from "Nuclear calcium signalling in the r..."
...in Central Nervous System Disorders...
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...Nuclear calcium, an important regulator of gene expression, plays a key role in the prosurvival effects of synaptic stimulation and is disrupted by extrasynaptic NMDAR activity (reviewed in Bading, 2013)....
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TL;DR: The results reveal the dynamic landscape of the stimulus-dependent transcriptional changes occurring across cell types in the visual cortex; these changes are probably critical for cortical function and may be sites of deregulation in developmental brain disorders.
Abstract: Activity-dependent transcriptional responses shape cortical function. However, a comprehensive understanding of the diversity of these responses across the full range of cortical cell types, and how these changes contribute to neuronal plasticity and disease, is lacking. To investigate the breadth of transcriptional changes that occur across cell types in the mouse visual cortex after exposure to light, we applied high-throughput single-cell RNA sequencing. We identified significant and divergent transcriptional responses to stimulation in each of the 30 cell types characterized, thus revealing 611 stimulus-responsive genes. Excitatory pyramidal neurons exhibited inter- and intralaminar heterogeneity in the induction of stimulus-responsive genes. Non-neuronal cells showed clear transcriptional responses that may regulate experience-dependent changes in neurovascular coupling and myelination. Together, these results reveal the dynamic landscape of the stimulus-dependent transcriptional changes occurring across cell types in the visual cortex; these changes are probably critical for cortical function and may be sites of deregulation in developmental brain disorders.
378 citations
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TL;DR: The best understood form of long-term potentiation is induced by the activation of the N-methyl-d-aspartate receptor complex, which allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and post Synaptic mechanisms to generate a persistent increase in synaptic strength.
Abstract: Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.
11,123 citations
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...Marchenko, S. M., Yarotskyy, V., Kovalenko, T. N., Kostyuk, P. G. & Thomas, R. C. Spontaneously active and InsP3-activated ion channels in cell nuclei from rat cerebellar Purkinje and granule neurones....
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TL;DR: It is demonstrated that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors, which triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.
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TL;DR: Diacylglycerol operates within the plane of the membrane to activate protein kinase C, whereas inositol trisphosphate is released into the cytoplasm to function as a second messenger for mobilizing intracellular calcium.
Abstract: There has recently been rapid progress in understanding receptors that generate intracellular signals from inositol lipids. One of these lipids, phosphatidylinositol 4,5-bisphosphate, is hydrolysed to diacylglycerol and inositol trisphosphate as part of a signal transduction mechanism for controlling a variety of cellular processes including secretion, metabolism, phototransduction and cell proliferation. Diacylglycerol operates within the plane of the membrane to activate protein kinase C, whereas inositol trisphosphate is released into the cytoplasm to function as a second messenger for mobilizing intracellular calcium.
5,712 citations