Astrocytes in the Synapse - Nurse or Key-Player? Rune Rasmussen Supervisor: Assoc. Prof. Jean-Francois Perrier Department of Neuroscience and Pharmacology
Astrocytes in the Synapse: Nurse or Key-Player?
Jun 03, 2015
Astrocytes have for decades been considered as non-excitable support cells of the central nervous system (CNS). However, this view has changed radically during the last thirty years. Astrocytes have come to the forefront of neuroscience in our attempt to gain a better understanding of the cellular mechanisms underlying synaptic transmission. Astrocytes express a variety of surface receptors for common neurotransmitters, e.g., glutamate and acetylcholine. Additionally, astrocytes respond to stimulation by releasing gliotransmitters such as glutamate. These properties have led to the concept of tripartite synapse involving bidirectional communication between neurons and astrocytes. This review aims at summarizing current evidence for how astrocytes are involved in modulating synaptic transmission within cortical regions of the CNS. The activation of metabotropic- and ionotropic receptors expressed in astrocytes triggers an increase in their intracellular Ca2+ concentration, which in turn promotes the release of glutamate. The astrocyte released glutamate stimulate either group I or II and III metabotropic glutamate receptors (mGluRs) on presynaptic terminals. Depending on the type of activated presynaptic mGluR, astrocytic glutamate may either potentiate or depress synaptic transmission. In summary, astrocytes are actively participating in the modulation of synaptic transmission within cortical regions of the CNS. Astrocytes may consequently be a potential therapeutic target for brain pathological illnesses, e.g., neurodegeneration during ischemic stroke.
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Astrocytes in the Synapse
- Nurse or Key-Player?
Rune Rasmussen
Supervisor: Assoc. Prof. Jean-Francois Perrier
Department of Neuroscience and Pharmacology
• Introduction to Astrocytes and Tripartite synapse
• Aim of project
• Main findings (exemplified through studies)
• Therapeutic applications
• Considerations
• Summary
Agenda
Glial cells (Greek “Glue”): Astrocytes, Oligodendrocytes and Microglia (CNS)
Astrocytes maintain synaptic homeostasis: e.g., K+ buffering (Kuffler, 1967)
Astrocytes the most numerous glial cell type
Occopy different spatial territories (Volterra & Meldolesi, 2005)
Do not fire action potentials (Obenheim et al., 2009)
(Volterra & Meldolesi, 2005)
Introduction
Astrocytes express receptors for neurotransmitters (Mothet at al., 2005; Araque, 2008)
Astrocytes release gliotransmitters ���(Bezzi et al., 1998; Navarrete et al., 2012)
=> Concept of a Tripartite Synapse (Araque & Haydon, 1999)
(Home-made illustration)
Presynaptic neuron
Postsynaptic neuron
Astrocyte
Nt
Gt
Gt
Introduction
i) Summarize main properties of cortical astrocytes
ii) Describe how neurotransmitters cause the release of the gliotransmitter glutamate
iii) Discuss how this glutamate is involved in modulation of synaptic transmission
Aim of Project
i) Summarize main properties of cortical astrocytes
ii) Describe how neurotransmitters cause the release of the gliotransmitter glutamate
iii) Discuss how this glutamate is involved in modulation of synaptic transmission
Aim of Project
i) Summarize main properties of cortical astrocytes
ii) Describe how neurotransmitters cause the release of the gliotransmitter glutamate
iii) Discuss how this glutamate is involved in modulation of synaptic transmission
Aim of Project
Properties of Astrocytes
Express metabotropic and ionotropic receptors (Rs) (Porter & McCarthy, 1996; Araque 2008)
Trigger intracellular Ca2+ elevation
Many metabotropic Rs coupled to Gαq and PLC-β
(Home-made illustration)
Properties of Astrocytes
Astrocytes base their excitability on intracellular variations in Ca2+ (Local or Global) (Volterra & Meldolesi, 2005)
Calcium signal in culture
(Nedergaard et al. 2013; Molnár et al. 2011)
Properties of Astrocytes
Calcium signal in vivo
Astrocytes release Glutamate
(Liu et al., 2004, PNAS)
Uncaging NP-EGTA in astrocyte trigger Ca2+ elevation
Astrocytes release Glutamate
Uncaging NP-EGTA in astrocyte trigger Ca2+ elevation
.. And this trigger glutamate release (activate Kainate Rs)
Astrocytes release Glutamate
(Liu et al., 2004, PNAS)
(Bezzi et al., 1998, Nature)
AMPA and mGluR agonist trigger glutamate release
Astrocytes release Glutamate
Mediated through type I mGluR and AMPAR activation, and in a Ca2+-dependent mechanism
Astrocytes release Glutamate
(Bezzi et al., 1998, Nature)
Modulation of Synaptic Transmission
(Home-made illustration)
Perea et al. (2007) setup
Modulation of Synaptic Transmission
ATP application triggered Ca2+
elevation in astrocytes
(Perea et al., 2007, Science)
Modulation of Synaptic Transmission
ATP application triggered Ca2+
elevation in astrocytes
And increased neurotransmitter release probability
Modulation of Synaptic Transmission
(Perea et al., 2007, Science)
ATP application triggered Ca2+
elevation in astrocytes
And increased neurotransmitter release probability
Through neuronal type I mGluR activation
Modulation of Synaptic Transmission
(Perea et al., 2007, Science)
Therapeutic application
Excitotoxicity plays a central role in the neuronal damage through activation of extrasynaptic NMDARs (Hardingham & Bading, 2010)
Therapeutic application
Excitotoxicity plays a central role in the neuronal damage through activation of extrasynaptic NMDARs (Hardingham & Bading, 2010)
Enhanced Ca2+ activity in astrocytic networks play a key role in the activation of extrasynaptic NMDARs in hippocampal slice neurons (Dong et al., 2013)
Therapeutic application
(Home-made illustration)
Astrocytic Ca2+ variations through the IP3 pathway does not affect synaptic transmission (Agulhon et al., 2010)
Considerations
Astrocytic Ca2+ variations through the IP3 pathway does not affect synaptic transmission (Agulhon et al., 2010)
Considerations
Photolysis of caged Ca2+, but not receptor-mediated Ca2+ signaling triggers astrocytic glutamate release (Smith et al., 2013, submitted)
Astrocytic Ca2+ variations through the IP3 pathway does not affect synaptic transmission (Agulhon et al., 2010)
Adult mice (> 3 weeks) do not express mGluR subtype 5 (Wei Sun et al. 2013)
Considerations
Photolysis of caged Ca2+, but not receptor-mediated Ca2+ signaling triggers astrocytic glutamate release (Smith et al., 2013, submitted)
Summary
• Astrocytes express metabotropic Rs (ATP and Glutamate) and base their excitability on variations in Ca2+ level
• Astrocytes release the gliotransmitter glutamate (IP3-Ca2+ dependent?)
Summary
• Astrocytes express metabotropic Rs (ATP and Glutamate) and base their excitability on variations in Ca2+ level
• Astrocytes release the gliotransmitter glutamate (IP3-Ca2+ dependent?)
• Release of astrocytic glutamate may potentiate synaptic transmission (Presynaptic mGluRs)
Summary
• Astrocytes express metabotropic Rs (ATP and Glutamate) and base their excitability on variations in Ca2+ level
• Astrocytes release the gliotransmitter glutamate (IP3-Ca2+ dependent?)
• Release of astrocytic glutamate may potentiate synaptic transmission (Presynaptic mGluRs)
Summary
• Astrocytes express metabotropic Rs (ATP and Glutamate) and base their excitability on variations in Ca2+ level
• Bi-directional communication between astrocytes and neurons might open up new therapeutic targets
(Hippocampal astrocytes: Bushong et al., 2002, J. Neurosci)
Rune RasmussenM.Sc. Stud. Human Biology
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