The interaction between astrocytes and excitatory synapses in health and disease
Author: Srivastava, Ipsit
Date: 2020-11-24
Location: Eva och Georg Klein salen, Biomedicum, Floor 3, Solnavägen 9, Karolinska Institutet, Solna
Time: 10.00
Department: Inst för neurobiologi, vårdvetenskap och samhälle / Dept of Neurobiology, Care Sciences and Society
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Thesis (12.06Mb)
Abstract
Synaptic transmission forms the basis of neuronal activity and astrocytes play an integral part in this process. Glutamate is the major excitatory neurotransmitter in the brain and an important function of astrocyte during excitatory synaptic activity involves the uptake of glutamate through astrocyte glutamate transporters (EAATs) and hence shaping the excitatory neurotransmission. Recently astrocytes have also been shown to affect a sustained form of inhibition. In this thesis, we study these aspects of astrocyte functions and their role in affecting the excitatory synapse. In addition, using animal models of diseases we describe how the astrocyte synapse interaction is affected in diseased conditions.
In the Paper I, we confirmed previous studies showing that astrocytes respond by a longlasting depolarization upon synaptic stimulation, mediated by an increase in extracellular potassium ions. We found that this long-lasting depolarization is enhanced when astrocytic glutamate transporters are blocked, whereas the neuronal EPSC is reduced under these conditions. Blocking the glutamate transporters reduces the AMPA receptor response whereas the NMDA receptor activation is increased, causing the enhancement seen in the astrocytic long-lasting depolarization. Since astrocyte glutamate transporters are impaired in many neurodegenerative diseases, this study gives us an idea about how the impairment of astrocytic glutamate transporters can influence synapse activity.
In the Paper II and III we used animal models of depression and AD respectively to understand the role of astrocytes in affecting synaptic transmission. In Paper II we used the well characterized FSL rat model of depression and investigated how reactive astrocytes affect inhibition by producing and releasing GABA. We found that tonic inhibition of pyramidal neurons is increased in the FSL rat while the synaptic plasticity is impaired. We also found that this tonic inhibition was reduced by blocking the astrocytic GABA synthesis or by chelating intracellular Ca[superscript2+] in astrocytes in slices from the FSL rat, giving evidence for increased astrocytic involvement in tonic inhibition in an animal model of depression. Furthermore, blocking of astrocytic GABA synthesis restored the impaired synaptic plasticity seen in FSL rats. In the Paper III, we explored the astrocyte mediated glutamate uptake in Alzheimer’s disease model using a knock in AD mouse model App[superscript NL-G-F]. Astrocytes displayed a reactive morphology, with swollen cell bodies and increased number of processes. We found that though there was an increase in the protein expression levels of astrocytic glutamate transporters (EAATs), they were functionally impaired as reflected by the glutamate transporter current recordings.
In the Paper I, we confirmed previous studies showing that astrocytes respond by a longlasting depolarization upon synaptic stimulation, mediated by an increase in extracellular potassium ions. We found that this long-lasting depolarization is enhanced when astrocytic glutamate transporters are blocked, whereas the neuronal EPSC is reduced under these conditions. Blocking the glutamate transporters reduces the AMPA receptor response whereas the NMDA receptor activation is increased, causing the enhancement seen in the astrocytic long-lasting depolarization. Since astrocyte glutamate transporters are impaired in many neurodegenerative diseases, this study gives us an idea about how the impairment of astrocytic glutamate transporters can influence synapse activity.
In the Paper II and III we used animal models of depression and AD respectively to understand the role of astrocytes in affecting synaptic transmission. In Paper II we used the well characterized FSL rat model of depression and investigated how reactive astrocytes affect inhibition by producing and releasing GABA. We found that tonic inhibition of pyramidal neurons is increased in the FSL rat while the synaptic plasticity is impaired. We also found that this tonic inhibition was reduced by blocking the astrocytic GABA synthesis or by chelating intracellular Ca[superscript2+] in astrocytes in slices from the FSL rat, giving evidence for increased astrocytic involvement in tonic inhibition in an animal model of depression. Furthermore, blocking of astrocytic GABA synthesis restored the impaired synaptic plasticity seen in FSL rats. In the Paper III, we explored the astrocyte mediated glutamate uptake in Alzheimer’s disease model using a knock in AD mouse model App[superscript NL-G-F]. Astrocytes displayed a reactive morphology, with swollen cell bodies and increased number of processes. We found that though there was an increase in the protein expression levels of astrocytic glutamate transporters (EAATs), they were functionally impaired as reflected by the glutamate transporter current recordings.
List of papers:
I. Ipsit Srivastava, Erika Vazquez-Juarez, Maria Lindskog. Reducing glutamate uptake in rat hippocampal slices enhances astrocytic membrane depolarization while down- regulating CA3-CA1 synaptic response. Frontiers in Synaptic Neuroscience. 2020 Aug 18;12:37.
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II. Ipsit Srivastava, Erika Vazquez-Juarez, Lukas Henning, Marta Gómez-Galán and Maria Lindskog. Blocking Astrocytic GABA Restores Synaptic Plasticity in Prefrontal Cortex of Rat Model of Depression. Cells. 2020 Jul 16;9(7):1705.
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III. Ipsit Srivastava, Marta Pereira Iglesias, Tamer Ayberk Kaya, Luis Enrique Arroyo-García, Per Nilsson, André Fisahn, Maria Lindskog, Silvia Maioli and Raúl Loera-Valencia. Increased levels but reduced function of astrocytic glutamate transporters in the hippocampus of the App[superscript NL-G-F] knock-in mice. [Manuscript]
I. Ipsit Srivastava, Erika Vazquez-Juarez, Maria Lindskog. Reducing glutamate uptake in rat hippocampal slices enhances astrocytic membrane depolarization while down- regulating CA3-CA1 synaptic response. Frontiers in Synaptic Neuroscience. 2020 Aug 18;12:37.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ipsit Srivastava, Erika Vazquez-Juarez, Lukas Henning, Marta Gómez-Galán and Maria Lindskog. Blocking Astrocytic GABA Restores Synaptic Plasticity in Prefrontal Cortex of Rat Model of Depression. Cells. 2020 Jul 16;9(7):1705.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Ipsit Srivastava, Marta Pereira Iglesias, Tamer Ayberk Kaya, Luis Enrique Arroyo-García, Per Nilsson, André Fisahn, Maria Lindskog, Silvia Maioli and Raúl Loera-Valencia. Increased levels but reduced function of astrocytic glutamate transporters in the hippocampus of the App[superscript NL-G-F] knock-in mice. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Lindskog, Maria
Co-supervisor: Brismar, Hjalmar; Ruas, Jorge
Issue date: 2020-11-02
Rights:
Publication year: 2020
ISBN: 978-91-8016-025-4
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