MGLUR5 Re-emergence on the Reactive Astrocyte: Structural and Functional Consequences in an Animal Model of Temporal Lobe Epilepsy

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Publication Type dissertation
School or College School of Medicine
Department Neurology
Author Umpierre, Anthony David
Title MGLUR5 Re-emergence on the Reactive Astrocyte: Structural and Functional Consequences in an Animal Model of Temporal Lobe Epilepsy
Date 2018
Description In early development, the metabotropic glutamate receptor 5 (mGluR5) plays a role in guiding astrocytes towards active synapses, ensheathing synapses, and increasing glutamate uptake. After early development, expression of mGluR5 is down-regulated and not observed on mature astrocytes. However, mGluR5 re-emergence is observed when astrocytes become reactive in multiple CNS diseases, including temporal lobe epilepsy (TLE). Understanding the role, function, and consequence of mGluR5 expression in the reactive astrocyte may elucidate a conserved astrocyte function across diseases of varied etiologies and shed light on whether astrocytes may contribute to disease progression, serve as protector, or exist as bystander. Astrocyte mGluR5 expression falls at the crossroads of this debate with existing literature suggesting astrocyte mGluR5 signaling contributes to disease progression in TLE by triggering excitatory gliotransmission; however, the alternative possibility that mGluR5 expression may recapitulate earlier developmental roles and function in a protective role has not been tested. Our early research in TLE models indicates astrocyte mGluR5 expression is coincidently observed alongside ensheathment and enhanced glutamate buffering, protective functions ascribed to mGluR5 signaling in development. The functional time course, impact, and consequences of astrocyte mGluR5 re-emergence are evaluated through multiple methodologies in this dissertation. Immuno-histochemical (IHC) analyses reveal mGluR5 is co-expressed by the astrocyte beginning 3 d after a brain insult, with high expression 1 week following injury. Two-photon calcium imaging experiments corroborate IHC findings and additionally indicate mGluR5 is functional and can induce calcium signaling when activated. To test for causative or mechanistic relationships between reactive astrocyte mGluR5 expression and protective functions, an astrocyte-specific mGluR5fl/fl mouse line was used to assess two major parameters. Single-cell, patch-clamp techniques reveal that reactive astrocytes have enhanced glutamate transport. Additionally, the presence of mGluR5 on the reactive astrocyte confers a further enhanced ability to transport glutamate during high-frequency stimulation. Long-term electroencephalogram (EEG) recording and video monitoring does not suggest astrocyte mGluR5 knockout impacts the propensity or severity of epilepsy development; however, knockdown at the population level was suboptimal. Overall findings suggest mGluR5 expression during reactive astrogliosis confers a gain of function in glial glutamate transport, potentially serving a neuroprotective role during epilepsy development.
Type Text
Publisher University of Utah
Subject Neurosciences; Pharmacology
Dissertation Name Doctor of Philosophy
Language eng
Rights Management (c) Anthoney David Umpierre
Format Medium application/pdf
ARK ark:/87278/s6n3503p
Setname ir_etd
Date Created 2020-02-13
Date Modified 2021-05-06
ID 1526105
Reference URL
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