A Quantitative Model of Purinergic Junctional Transmission of Calcium Waves in Astrocyte Networks

Bennett, Maxwell R.; Farnell, L.; Gibson, W.G.

doi:10.1529/biophysj.105.062968

Cited by 92 publications

(104 citation statements)

References 68 publications

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“…Often synaptic responses in brain neurons mediated by endogenously released ATP are outweighed by those mediated by glutamate (Edwards et al, 1992;Nieber et al, 1997;Pankratov et al, 1998;Khakh, 2001;Mori et al, 2001;North, 2002;Pankratov et al, 2002Pankratov et al, , 2007. However, based on the data presented in this and previous studies, ATP appears to dominate over glutamate with respect to astrocyte signaling (Koizumi et al, 2003;Bowser and Khakh, 2004;Bennett et al, 2005;Bennett et al, 2006;Fields and Burnstock, 2006). In summary, the data presented here for astrocyte cultures extends our previous work in acute brain slices (Bowser and Khakh, 2004) and suggests that ATP is the predominant cause of intercellular calcium waves.…”

Section: Discussionsupporting

confidence: 76%

Vesicular ATP Is the Predominant Cause of Intercellular Calcium Waves in Astrocytes

Bowser¹,

Khakh²

2007

J Cell Biol

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Brain astrocytes signal to each other and neurons. They use changes in their intracellular calcium levels to trigger release of transmitters into the extracellular space. These can then activate receptors on other nearby astrocytes and trigger a propagated calcium wave that can travel several hundred micrometers over a timescale of seconds. A role for endogenous ATP in calcium wave propagation in hippocampal astrocytes has been suggested, but the mechanisms remain incompletely understood. Here we explored how calcium waves arise and directly tested whether endogenously released ATP contributes to astrocyte calcium wave propagation in hippocampal astrocytes. We fi nd that vesicular ATP is the major, if not the sole, determinant of astrocyte calcium wave propagation over distances between ‫001ف‬ and 250 μm, and ‫51ف‬ s from the point of wave initiation. These actions of ATP are mediated by P2Y1 receptors. In contrast, metabotropic glutamate receptors and gap junctions do not contribute signifi cantly to calcium wave propagation. Our data suggest that endogenous extracellular astrocytic ATP can signal over broad spatiotemporal scales. I N T R O D U C T I O NAstrocytes are an integral part of the brain, where they form connections with blood vessels, other glia, and neurons (Haydon, 2001). In contrast to neurons, which exhibit electrical excitability, astrocytes display "calcium excitability" (Cornell-Bell et al., 1990), which is manifest as transient or prolonged elevations in intracellular calcium levels ([Ca 2+ ] i ). These can be spontaneous or triggered in response to specifi c neurotransmitters (Cornell-Bell et al., 1990). Spontaneous intracellular calcium transients [Ca 2+ ] i have been described in cultured astrocytes (Cornell-Bell et al., 1990;Charles et al., 1991), acute brain slices where the cellular architecture remains virtually intact (Porter and McCarthy, 1996), as well as in vivo in the cortex (Hirase et al., 2004;Tian et al., 2005Tian et al., , 2006Wang et al., 2006). In acute slices and in cultured astrocytes, waves of elevated [Ca 2+ ] i can pass between astrocytes (Charles et al., 1991;Newman and Zahs, 1997;Guthrie et al., 1999), and are often referred to as intercellular calcium waves. Several pathways have been proposed to mediate calcium waves, including diffusion of Ca 2+ and/or inositol triphosphate through membrane gap junctions between adjoining astrocytes (Scemes et al., 2000). Additionally, it has been suggested that astrocytic release of ATP or glutamate into the extracellular space, and subsequent activation of their respective receptors on neighboring astrocytes may also underlie calcium wave propagation (Fellin et al., 2006). However, it remains unclear if ATP, gap junctions, and glutamate contribute equally to calcium wave propagation, or if any one mechanism predominates (Charles, 1998;Scemes and Giaume, 2006).In the present experiments we studied hippocampal cultures because astrocyte calcium transients are well described in this model system (Charles, 1998;Fields and Burnstock,...

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Section: Discussionsupporting

confidence: 76%

Vesicular ATP Is the Predominant Cause of Intercellular Calcium Waves in Astrocytes

Bowser¹,

Khakh²

2007

J Cell Biol

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“…88,89 Importantly, glial Ca 2ϩ signals are capable of propagating though glial syncytia, 90 -92 using several complimentary mechanisms that include diffusion of InsP 3 through gap junctions, or release and extracellular diffusion of gliotransmitter. [93][94][95][96] These propagating glial Ca 2ϩ waves are the most thoroughly investigated mechanism of long-range glial signaling; nonetheless, many other molecules (e.g., metabolic substrates, ATP, or other second messengers) can also participate in signaling within astroglial circuits.…”

Section: Signaling In Neuronal-glial Circuits 1) Glial Cells Express mentioning

confidence: 99%

Astrocytes in Alzheimer's Disease

et al. 2010

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Summary:The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs.Astroglial cells are engaged in neurological diseases by determining the progression and outcome of neuropathological process. Astrocytes are specifically involved in various neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and various forms of dementia. Recent evidence suggest that early stages of neurodegenerative processes are associated with atrophy of astroglia, which causes disruptions in synaptic connectivity, disbalance in neurotransmitter homeostasis, and neuronal death through increased excitotoxicity. At the later stages, astrocytes become activated and contribute to the neuroinflammatory component of neurodegeneration.

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“…Our single cell model, introduced in (Barrack et al, 2014), is comprised of a cell cycle component based on the model of Obeyesekere et al (1999) and an ATP mediated calcium release component based on the model of Bennett et al (2005). The cell cycle model includes five dynamical variables including Cyclin D/Cdk4, Cy- clin E/Cdk2, unphosphorylated retinoblastoma tumour suppressor protein (RB) and phosphorylated RB bound to the E2F transcription factor.…”

Section: The Modelmentioning

confidence: 99%

Modelling cell cycle synchronisation in networks of coupled radial glial cells

Barrack

Thul

Owen

2015

Journal of Theoretical Biology

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Radial glial cells play a crucial role in the embryonic mammalian brain. Their proliferation is thought to be controlled, in part, by ATP mediated calcium signals. It has been hypothesised that these signals act to locally synchronise cell cycles, so that clusters of cells proliferate together, shedding daughter cells in uniform sheets. In this paper we investigate this cell cycle synchronisation by taking an ordinary differential equation model that couples the dynamics of intracellular calcium and the cell cycle and extend it to populations of cells coupled via extracellular ATP signals. Through bifurcation analysis we show that although ATP mediated calcium release can lead to cell cycle synchronisation, a number of other asynchronous oscillatory solutions including torus solutions dominate the parameter space and cell cycle synchronisation is far from guaranteed. Despite this, numerical results indicate that the transient and not the asymptotic behaviour of the system is important in accounting for cell cycle synchronisation. In particular, quiescent cells can be entrained on to the cell cycle via ATP mediated calcium signals initiated by a driving cell and crucially will cycle in near synchrony with the driving cell for the duration of neurogenesis. This behaviour is highly sensitive to the timing of ATP release, with release at the G 1 /S phase transition of the cell cycle far more likely to lead to near synchrony than release during mid G 1 phase. This result, which suggests that ATP release timing is critical to radial glia cell cycle synchronisation may help to understand normal and pathological brain development.

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A Quantitative Model of Purinergic Junctional Transmission of Calcium Waves in Astrocyte Networks

Cited by 92 publications

References 68 publications

Vesicular ATP Is the Predominant Cause of Intercellular Calcium Waves in Astrocytes

Vesicular ATP Is the Predominant Cause of Intercellular Calcium Waves in Astrocytes

Astrocytes in Alzheimer's Disease

Modelling cell cycle synchronisation in networks of coupled radial glial cells

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