The Importance of astrocyte‐derived purines in the modulation of sleep

Blutstein, Tamara

doi:10.1002/glia.22422

Cited by 66 publications

(41 citation statements)

References 53 publications

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“…This notion is supported by in vivo studies that used molecular genetics targeted to the astrocyte and showed that astrocytes modulate sleep homeostasis (Halassa et al 2009;Blutstein and Haydon 2013). Sleep is controlled by at least two substantial processes: the circadian oscillator and the sleep homeostat.…”

Section: Sleep Arousal and Vigilancementioning

confidence: 94%

How Do Astrocytes Participate in Neural Plasticity?

Haydon

2014

Cold Spring Harb Perspect Biol

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126

104

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Section: Sleep Arousal and Vigilancementioning

confidence: 94%

How Do Astrocytes Participate in Neural Plasticity?

Haydon

2014

Cold Spring Harb Perspect Biol

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126

104

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“…Adenosine is a key regulator of sleep homeostasis and sleep-associated cognitive performance (Basheer et al, 2004; Bjorness et al, 2009; Blutstein and Haydon, 2012; Halassa et al, 2009; Porkka-Heiskanen et al, 1997). A 1 R agonists and antagonists induce and suppress sleep, respectively, via basal forebrain-mediated mechanisms (Benington et al, 1995; Ticho and Radulovacki, 1991; Virus et al, 1990).…”

Section: Adenosine-dependent Mechanisms and Therapeutic Applicationsmentioning

confidence: 99%

Comorbidities in Neurology: Is adenosine the common link?

Boison

Aronica

2015

Neuropharmacology

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Comorbidities in Neurology represent a major conceptual and therapeutic challenge. For example, temporal lobe epilepsy (TLE) is a syndrome comprised of epileptic seizures and comorbid symptoms including memory and psychiatric impairment, depression, and sleep dysfunction. Similarly, Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are accompanied by various degrees of memory dysfunction. Patients with AD have an increased likelihood for seizures, whereas all four conditions share certain aspects of psychosis, depression, and sleep dysfunction. This remarkable overlap suggests common pathophysiological mechanisms, which include synaptic dysfunction and synaptotoxicity, as well as glial activation and astrogliosis. Astrogliosis is linked to synapse function via the tripartite synapse, but astrocytes also control the availability of gliotransmitters and adenosine. Here we will specifically focus on the ‘adenosine hypothesis of comorbidities’ implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine. We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS. We discuss a transgenic ‘comorbidity model’, in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation. We conclude that dysfunction of adenosine signaling is common in neurological conditions, that adenosine dysfunction can explain comorbid phenotypes, and that therapeutic adenosine augmentation might be effective for the treatment of comorbid symptoms in multiple neurological conditions.

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“…Why? Another link between signaling and metabolism is adenosine, a degradation product of purine nucleotides but also a major neuromodulator involved in the coordination of synaptic networks, neurovascular coupling, and the physiology of sleep (Pascual et al 2005;Blutstein and Haydon 2013). Further, cross talk is provided by lactate, which diffuses beyond the active zone and modifies the activity of neurons and astrocytes in neighboring regions acting via the NADH/NAD þ ratio, ion channels, and the G protein-coupled lactate receptor HCA1.…”

Section: Metabolism and Signalingmentioning

confidence: 99%

The Astrocyte: Powerhouse and Recycling Center

Weber

Barros

2015

Cold Spring Harb Perspect Biol

157

121

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Brain metabolism is characterized by fuel monodependence, high-energy expenditure, autonomy from the rest of body, local recycling, and marked division of labor between cell types. Although neurons spend most of the brain's energy on signaling, astrocytes bear the brunt of the metabolic load, controlling the composition of the interstitial fluid, supplying neurons with energy substrates and precursors for biosynthesis, and recycling neurotransmitters, oxidized scavengers, and other waste products. Outstanding questions in this field are the role of oligodendrocytes, the metabolic behavior of the different subtypes of astrocytes during development and disease, and the emerging notion that metabolism may participate directly in information processing. T he energy requirements of the central nervous system (CNS) are very high compared with those of other organs. Although the brain accounts for merely 2% of body weight, it receives 15% of cardiac output, and uses 20% of the oxygen and 25% of the glucose of the total body turnover (Magistretti 2008). A special microarchitecture has evolved to support this extreme need, in which glial cells play a central role (Fig. 1). The microvasculature consists of a complex and dense network of highly interconnected blood vessels (Weber et al. 2008;Blinder et al. 2013) to ensure adequate delivery of oxygen and glucose. Although oxygen diffuses freely into the parenchyma, glucose and other hydrophilic energy substrates are translocated across membranes via specific transporter proteins (Fig. 1). The astrocyte is a polarized cell. One set of astrocytic processes ensheaths the vasculature and a second set reaches toward the synapse, the site of highest energy demand (Harris et al. 2012). Much of the ATP produced in the brain is spent by neurons on the recovery of ion gradients challenged by postsynaptic potentials, with a smaller investment in action potentials and neurotransmitter recycling (Harris et al. 2012). Astrocytes consume considerable energy for their own needs and the cycling of metabolically relevant substances for neurons. These metabolic processes in astrocytes and neurons are the basis for brain mapping using functional magnetic resonance imaging and positron emission tomography (PET)-methods that capture local metabolism either directly or indirectly via hemodynamic changes (Magistretti 2008;Belanger et al. 2011a). Levels of energy consumption in the whole brain are almost constant. However, individual neurons can increase their consumption dramatically. For example, a striatal neuron may Overview of astrocytic metabolism. (Inset) Astrocytes (green) reside between blood vessels (red) and neurons (yellow). Neurons and oligodendrocytes (blue) are not in direct contact with vessels. Astrocytes form metabolic domains and are coupled by gap junctions, through which they exchange metabolites and ions. Energy: The main energy substrate of the brain is glucose (glc), which crosses the endothelium and enters astrocytes via the glucose transporter GLUT1. Glucose is converted b...

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The Importance of astrocyte‐derived purines in the modulation of sleep

Cited by 66 publications

References 53 publications

How Do Astrocytes Participate in Neural Plasticity?

How Do Astrocytes Participate in Neural Plasticity?

Comorbidities in Neurology: Is adenosine the common link?

The Astrocyte: Powerhouse and Recycling Center

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