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Nuclear Calcium Signalling in the Regulation of Brain Function

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Nuclear Calcium Signalling in the Regulation of Brain Function REVIEWS Nuclear calcium signalling in the regulation of brain function Hilmar Bading 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. Calcium signals are used in virtually all cells to carry In this Review, I summarize recent findings support‑ information and regulate numerous biochemical pro‑ ing this hypothesis and outline the role of nuclear cal‑ cesses1. Life would be impossible without calcium ions cium as an evolutionarily conserved signal that is used in making the heart beat, causing skeletal muscle to con‑ many cell types and organisms to control signal‑induced, tract, activating the immune system for defence against long‑lasting adaptive responses. A general overview of pathogens or stimulating the release of neurotransmitters the various other mechanisms by which signals can be to mediate cognitive functions. Calcium signals can act relayed to the cell nucleus in neurons can be found in locally near the site of calcium entry into the cytoplasm REFS 10,11. but are also often transmitted over long distances and can reach the cell nucleus2. Synapse-to-nucleus signalling Nuclear calcium has emerged as one of the most Adaptation is a characteristic of life. Virtually all organ‑ potent regulators of neuronal gene expression3. Synaptic isms adjust to changes in their environment, and this stimuli that give rise to increased nuclear calcium levels may be advantageous or even essential to cope with new in a neuron activate gene programmes that can induce conditions. For such changes to be long lasting, the cells’ structural and functional alterations in the same cell gene expression patterns must be reprogrammed appro‑ and in the network to which it belongs. These changes priately. One example of a transcription‑dependent adap‑ include the build‑up of a neuroprotective shield4 or a tation in the nervous system is the sensitization of the gill persistent increase in the efficacy of synaptic transmis‑ withdrawal reflex in the sea slug Aplysia californica12,13. sion, which is considered to be a cellular correlate of In this non‑associative learning paradigm, the pairing behavioural adaptations, such as learning, memory or of a touch to the siphon with a brief electrical shock addiction5–8. Several years ago it was proposed that both to the head results in an exaggerated gill withdrawal Department of Neurobiology, activity‑driven changes in functional properties and response. If the paired stimulation is applied repeatedly, Interdisciplinary Centre for Neurosciences (IZN), the generation of nuclear calcium transients are caus‑ this change in the behaviour of the animal persists for University of Heidelberg, INF ally linked and that nuclear calcium is the signal that days. This long‑lasting form of sensitization was found 364, 69120 Heidelberg, switches on the genomic components needed for the to be dependent on gene transcription and new protein Germany. long‑term implementation of neuroadaptations9. This synthesis14. This was a landmark discovery showing that e-mail: Hilmar.Bading@ ‘nuclear calcium hypothesis’ (REF. 9) predicted that per‑ the process of ‘learning’ and the resulting long‑term uni-hd.de doi:10.1038/nrn3531 sistent adaptations — both at the cellular and the behav‑ adaptation requires a dialogue between synapses and the Published online ioural level — take place when calcium enters the cell cell nucleus. Subsequent studies revealed that signalling 14 August 2013 nucleus to activate transcription. to the nucleus and the activation of genomic responses NATURE REVIEWS | NEUROSCIENCE VOLUME 14 | SEPTEMBER 2013 | 593 © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS are also required for olfactory associative learning in the The evolutionary emergence of voltage‑sensitive gat‑ fruitfly Drosophila melanogaster 15,16, learning of spatial ing in plasma membrane calcium channels was probably cues in rodents17 and for late‑phase long-term potentiation also important for the selection of calcium as a neuronal or depression of synaptic efficacy, which may underlie signal transducer. This biophysical feature provides the learning18,19. mechanistic basis for a direct coupling between the main Addiction and chronic pain are also adaptive responses function of neurons (that is, the depolarization of their of the nervous system, in which the relevant stimulus (an membranes and the firing of action potentials) with a addictive drug or the prolonged irritation of sensory rise in intracellular calcium levels. Thus, without the need neurons) induces changes in synaptic transmission that for any intermediate enzymatic reaction, an intracellular functionally alter the participating neuronal network signal that can mirror the neurons’ electrical activity state and lead to pathological behaviour6,8,20. As with classical is generated. Calcium transients caused by calcium entry learning‑associated events, signalling to the nucleus and from the extracellular space can be further enhanced by the resulting genomic responses are crucial for main‑ ryanodine receptor‑mediated, calcium‑induced calcium taining the new—in this case pathological—state21,22. release from the ER or the Golgi apparatus33,34. A second Further examples of adaptive responses associated with exit route for calcium from the intracellular stores (ER the activation of nuclear signalling pathways and sig‑ and Golgi apparatus) is through the inositol trisphos‑ nal‑regulated transcription include activity‑dependent phate (IP3) receptor33,34. The opening of IP3 receptors neuronal survival3,23–25, light‑induced changes in circa‑ may be associated with synaptic activation if the neuro‑ dian rhythmicity26,27, neural repair after injury28,29 and transmitter involved stimulates G protein‑coupled recep‑ neuronal activity‑induced neurogenesis30. Calcium has tors (GPCRs) that activate phospholipase C, the enzyme a central role as the mediator of the intracellular informa‑ that cleaves phosphatidylinositol‑4,5‑biphosphate to tion flow in virtually all forms of neuroadaptation. Within generate IP3 as well as diacyglycerol, which stimulates the nucleus, calcium signals integrate synapse‑to‑nucleus protein kinase C35. communication and translate particular activity patterns Downstream of the initial activity‑induced calcium into altered gene transcription. transient, signal processing can diversify and engage other molecules. For example, increases in cyclic AMP Why calcium and why nuclear calcium? (cAMP) and nitric oxide can be generated through There are several reasons for the selection of calcium as a calcium‑sensitive adenylyl cyclases and nitric oxide key second messenger during evolution, and these have synthases, respectively36–39. Calcium signalling also been reviewed in detail elsewhere31,32. Briefly, as a diva‑ feeds into classical receptor tyrosine kinase‑regulated lent cation, calcium can generate more stable complexes pathways, including the RAS–extracellular signal‑reg‑ with other compounds than can monovalent ions such ulated kinase (ERK)/mitogen‑activated protein (MAP) as sodium, potassium or chloride. Compared with the kinase cascade40,41, which calcium activates by stimulat‑ divalent magnesium ion, calcium has a larger radius and ing neuronal RAS‑specific guanine nucleotide‑releasing Long-term potentiation a more complex electron shell configuration. This pro‑ factor (RASGRF; also known as Ras guanine nucleo‑ A long-lasting (hours or days) 42 increase in synaptic efficacy vides the flexibility that allows it to readily form bonds tide exchange factor) and by inhibiting a synaptic 43 that is most commonly with coordination sites that have irregular geometry, such RAS GTPase‑activating protein . However, the spread measured as the response of as those characteristic of biological macromolecules. In of these secondary calcium signalling events is generally neurons to stimulation of their addition, proteins can form compact binding cavities rather limited because they are primarily mediated by presynaptic afferents after a matching the dimensions of calcium, which is more dif‑ diffusion and are subject to rapid enzymatic inactiva‑ brief patterned stimulus (for 44 example, a 1-s, 100-Hz ficult to achieve for the smaller magnesium ion owing to tion . Although calcium signals also face elimination by stimulus). the limited structural flexibility of proteins. Thus, owing calcium uptake and other clearance systems, they can, to its size and particular coordination chemistry (also see within milliseconds, bridge long distances of up to several Nuclear envelope REFS 31,32), calcium is far better suited than other ions hundred micrometres to reach the signalling end point, Two membranes (outer and 45–50 nuclear
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