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postgraduate thesis: Neuron-astroglial communications : NMDA-induced proheparanase modulation of synaptic strength
Title | Neuron-astroglial communications : NMDA-induced proheparanase modulation of synaptic strength |
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Authors | |
Advisors | |
Issue Date | 2018 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Chow, W. H. [鄒永浩]. (2018). Neuron-astroglial communications : NMDA-induced proheparanase modulation of synaptic strength. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Recent findings of neuronal expression of heparanase and the possible role of perisynaptic
proheparanase in triggering decrease in both basal and long-term
potentiation of synaptic strength set the stage for this work to find sources of
proheparanase in the synaptic environment in the context of the tripartite synapse,
comprising pre- and post-synaptic neurons and peri-synaptic astrocytes.
With highly purified hippocampal neurons forming networks at around 21 DIV and
low-dose NMDA (glutamate analogue) to chemically induce long-term depression of
synaptic strength, proheparanase secreted into the serum-free medium was found to
be twice that of controls. Similar treatment of purified astrocytes in culture showed
medium proheparanase 5-fold that of controls, suggesting astrocytic capacity for response to low-dose NMDA exceeding that of neurons. Taking the cue that
exosomes carry membrane-clustered proheparanase for release into the extracellular
environment, the exosome fraction was recovered from the conditioned medium of
astrocyte cultures following differential centrifugation and then ultracentrifugation.
Indeed, proheparanase was detectable in the exosome fraction as marked by
immunopositivities for Lamp1, TSG101 and Alix. Phorbol ester (activator of protein
kinase C pathway) and low-dose NMDA treatments of hippocampal neurons
triggered additive effects on release of proheparanase into the extracellular
environment, via exocytosis and exosomes respectively. Exosomal proheparanse
affected a site-specific phosphorylation of GluA2-containing AMPA receptors. By
contrast, long-term deficiency of proheparanase in hippocampal neurons decreased
the GluA2 site-specific phosphorylation and increased total GluA2-containing AMPA
receptor level. The study presented here provides evidence that astrocytes can
respond to the spill-over of glutamate during neuronal transmission and react via
proheparanase to modulate synaptic transmission. Hence, the current study supports
and delineates a new means by which astrocytes can modulate synaptic strength. The
finding provides insights into astrocytes as a potential target for treating cognitive
impairments involving the hippocampus.
|
Degree | Doctor of Philosophy |
Subject | Astrocytes Synapses |
Dept/Program | Biomedical Sciences |
Persistent Identifier | http://hdl.handle.net/10722/294774 |
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Shum, DKY | - |
dc.contributor.advisor | Chan, YS | - |
dc.contributor.author | Chow, Wing Ho | - |
dc.contributor.author | 鄒永浩 | - |
dc.date.accessioned | 2020-12-10T03:39:22Z | - |
dc.date.available | 2020-12-10T03:39:22Z | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | Chow, W. H. [鄒永浩]. (2018). Neuron-astroglial communications : NMDA-induced proheparanase modulation of synaptic strength. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/294774 | - |
dc.description.abstract | Recent findings of neuronal expression of heparanase and the possible role of perisynaptic proheparanase in triggering decrease in both basal and long-term potentiation of synaptic strength set the stage for this work to find sources of proheparanase in the synaptic environment in the context of the tripartite synapse, comprising pre- and post-synaptic neurons and peri-synaptic astrocytes. With highly purified hippocampal neurons forming networks at around 21 DIV and low-dose NMDA (glutamate analogue) to chemically induce long-term depression of synaptic strength, proheparanase secreted into the serum-free medium was found to be twice that of controls. Similar treatment of purified astrocytes in culture showed medium proheparanase 5-fold that of controls, suggesting astrocytic capacity for response to low-dose NMDA exceeding that of neurons. Taking the cue that exosomes carry membrane-clustered proheparanase for release into the extracellular environment, the exosome fraction was recovered from the conditioned medium of astrocyte cultures following differential centrifugation and then ultracentrifugation. Indeed, proheparanase was detectable in the exosome fraction as marked by immunopositivities for Lamp1, TSG101 and Alix. Phorbol ester (activator of protein kinase C pathway) and low-dose NMDA treatments of hippocampal neurons triggered additive effects on release of proheparanase into the extracellular environment, via exocytosis and exosomes respectively. Exosomal proheparanse affected a site-specific phosphorylation of GluA2-containing AMPA receptors. By contrast, long-term deficiency of proheparanase in hippocampal neurons decreased the GluA2 site-specific phosphorylation and increased total GluA2-containing AMPA receptor level. The study presented here provides evidence that astrocytes can respond to the spill-over of glutamate during neuronal transmission and react via proheparanase to modulate synaptic transmission. Hence, the current study supports and delineates a new means by which astrocytes can modulate synaptic strength. The finding provides insights into astrocytes as a potential target for treating cognitive impairments involving the hippocampus. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Astrocytes | - |
dc.subject.lcsh | Synapses | - |
dc.title | Neuron-astroglial communications : NMDA-induced proheparanase modulation of synaptic strength | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Biomedical Sciences | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2018 | - |
dc.identifier.mmsid | 991044306522803414 | - |