Key Points
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Nuclear calcium is an important mediator of activity-dependent gene expression in the nervous system. It serves as a signalling end point in synapse-to-nucleus communication and activates gene programmes needed for the long-term implementation of many neuroadaptations, including memory consolidation, acquired neuroprotection and the development of chronic pain. The requirement of nuclear calcium signals for long-term memory formation is evolutionarily conserved from flies to mammals.
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The mechanism through which synaptic activity leads to increases in the intranuclear calcium concentration involves stimulation of synaptic NMDA receptors, generation of backpropagating action potentials and the opening of voltage-gated calcium channels. Nuclear calcium transients may also be initiated or enhanced by calcium release from intracellular calcium stores mediated by inositol triphosphate or ryanodine receptors.
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Nuclear calcium is one of the most potent regulators of gene expression. It controls the activity or nuclear localization of several transcriptional regulators (which include CREB (cyclic AMP-responsive element-binding protein), CBP (CREB-binding protein), class IIa HDACs (histone deactylases) and MECP2 (metyhyl-CpG-binding protein 2)) that either generate or interpret chromatin modifications.
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The target gene pool of nuclear calcium signalling comprises nearly 200 genes that function, for example, in the regulation of dendrite architecture and spine density and shape. The neuroprotective activity of nuclear calcium signalling appears to be mediated by a set of genes that render mitochondria more resistant to harmful conditions.
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The effects of nuclear calcium on gene regulation and neuroprotection are antagonized by the stimulation of extrasynaptic NMDA receptors that trigger transcriptional shut-off and cell death pathways.
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Dysfunctioning of nuclear calcium signalling, referred to as 'nuclear calciopathy', may be a common factor in the aetiology of neurodegenerative and neuropsychiatric conditions. The modulation of nuclear calcium signalling may be a novel therapeutic strategy for the treatment of neurological disorders.
Abstract
Synaptic activity initiates biochemical processes that have various outcomes, including the formation of memories, increases in neuronal survival and the development of chronic pain and addiction. Virtually all activity-induced, long-lasting adaptations of brain functions require a dialogue between synapses and the nucleus that results in changes in gene expression. Calcium signals that are induced by synaptic activity and propagate into the nucleus are a major route for synapse-to-nucleus communication. Recent findings indicate that diverse forms of neuroadaptation require calcium transients in the nucleus to switch on the necessary genomic programme. Deficits in nuclear calcium signalling as a result of a reduction in synaptic activity or increased extrasynaptic NMDA receptor signalling may underlie the aetiologies of various diseases, including neurodegeneration and cognitive dysfunction.
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Acknowledgements
This Review is dedicated to my thesis advisor, W. Hasselbach and to E. Carafoli, both pioneers in the field of calcium signalling. I am very grateful to the many excellent young scientists who I have had the pleasure to work with over the years; without them it would not have been possible to establish the function of nuclear calcium in biological adaptations. I would like to thank the members of my laboratory for comments on the manuscript and in particular A. Hagenston-Hertle, B. Buchthal and C. P. Bengtson for their help with the design of the figures. The work in the author's laboratory is supported by the Deutsche Forschungsgemeinschaft, the Alexander von Humboldt Foundation and the European Research Council Advanced Grant.
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Glossary
- Long-term potentiation
-
A long-lasting (hours or days) increase in synaptic efficacy that is most commonly measured as the response of neurons to stimulation of their presynaptic afferents after a brief patterned stimulus (for example, a 1-s, 100-Hz stimulus).
- Nuclear envelope
-
Two membranes (outer and inner) surrounding the cell nucleus; the outer membrane is continuous with the endoplasmic reticulum. The outer nuclear membrane is connected to the inner nuclear membrane at the nuclear pore complexes.
- Nuclear pore complexes
-
Large multiprotein complexes that form channels in the nuclear envelope of a eukaryotic cell. Nuclear pore complexes span the inner and outer nuclear membranes and allow the exchange of ions, metabolites and macromolecules between the nucleus and the cytoplasm.
- Excitatory postsynaptic potential
-
The depolarizing voltage response of a postsynaptic neuron to a neurotransmitter released by one or more afferent presynaptic terminals that moves the membrane potential towards the action potential threshold.
- Electrotonic signal
-
A passively propagating electrical impulse. It differs from an action potential in that its spread of charge along a cellular membrane does not involve the activation of voltage-dependent transmembrane currents.
- Histone acetyltransferase
-
(HAT). An enzyme that catalyses the addition of an acetyl group to specific lysine residues in histones. In general, increased levels of histone acetylation are associated with the activation of gene expression. Many HATs function as transcriptional co-activators.
- Histone deacetylases
-
(HDACs). Enzymes that remove the acetyl groups from lysine residues that are located at the amino termini of histones. In general, decreased levels of histone acetylation are associated with the repression of gene expression.
- EF hand calcium-binding domain
-
A highly conserved calcium-binding domain, comprising two helices (E and F after the fifth and sixth helices of parvalbumin) that are linked by a short acidic calcium-binding loop that coordinates the calcium ion in a pentagonal bipyramidal arrangement. EF hands are found in many calcium-binding proteins, including calmodulin.
- Transcriptome
-
The complete set of RNA molecules produced by a cell or a population of cells at a given time point.
- Acquired neuroprotection
-
A synaptic activity-driven and gene transcription-dependent enhancement of the ability of neurons to survive harmful conditions.
- Memory consolidation
-
A molecular mechanism by which memories are converted into an enduring form. This process typically lasts for a few hours after learning and requires new protein synthesis.
- Contextual fear conditioning
-
A hippocampus-dependent form of Pavlovian conditioning in which rodents learn to associate a specific spatial context with the administration of an aversive stimulus: for example, an electrical footshock. When re-exposed to the same environment, animals will demonstrate a fear response: for example, freezing.
- Oxygen–glucose deprivation
-
An in vitro model of cerebral stroke in which cultured neurons or brain slices are exposed to media containing insufficient amounts of glucose and oxygen, which leads to cell death.
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Bading, H. Nuclear calcium signalling in the regulation of brain function. Nat Rev Neurosci 14, 593–608 (2013). https://doi.org/10.1038/nrn3531
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DOI: https://doi.org/10.1038/nrn3531
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