Dissertation/Thesis Abstract

Maturation of Astrocyte Glutamate Regulation Drives the Development of Cortical Inhibition
by Hanson, Elizabeth, Ph.D., Sackler School of Graduate Biomedical Sciences (Tufts University), 2017, 193; 10261473
Abstract (Summary)

The goal of this project is to examine the developmental regulation of astrocytic glutamate uptake in the cortex and determine to what extent dynamic glutamate regulation is an important feature of cortical development. This is an important question because homeostatic functions of astrocytes, like glutamate regulation, are actively maturing in the postnatal cortex. Currently, though, little is known about functional glutamate regulation in the neonatal cortex. To address this gap in knowledge, I measured the maturation of functional glutamate uptake in the developing cortex using electrophysiological recordings of glutamate transporter currents in astrocytes. I found that glutamate clearance is slow in the neonatal cortex and, furthermore, this slow glutamate clearance is permissive for extrasynaptic NMDA receptor activation. Interestingly, we found that the developmental expression of glutamate transporters is disrupted by neonatal injury in the freeze lesion (FL) model. I hypothesized that disruptions in glutamate regulation during the injury-induced latent period may underlie the pathological development that leads to cortical hyperexcitability after FL. I found no indication that synaptic or phasic glutamate clearance was disrupted, though changes in ambient glutamate remain to be investigated.

The major question arising from this work is what the functional role of slow glutamate uptake might be in normal cortical development. I hypothesized that reduced clearance in the neonatal cortex may be allowing ambient glutamate accumulation. To test this, I used electrophysiological assessments of tonic NMDA receptor-mediated currents in cortical pyramidal cells and GABAergic interneurons (INs). I discovered that ambient glutamate tonically activates NMDA receptors containing GluN2C and/or GluN2D subunits. These receptors are expressed specifically on cortical INs, therefore specifically INs are tonically depolarized. Additionally, the tonic current is strongest in cortical INs at P7, at the peak of GluN2D expression. Finally, blockade of GluN2C/D-containing NMDA receptors with DQP-1105, from P7-9, causes lasting reductions in GABAergic synapse number and IN dendritic complexity as well as an increase in cortical hyperexcitability.

In summary, my studies describe a novel mechanism by which developmental regulation of astrocytic glutamate clearance creates a permissive environment for extrasynaptic and tonic glutamate signaling, which is necessary for the development of cortical inhibition.

Indexing (document details)
Advisor: Dulla, Chris, Jackson, Rob
Commitee: Chen, Chinfei, Cox, Dan, Yang, Yongjie
School: Sackler School of Graduate Biomedical Sciences (Tufts University)
Department: Neuroscience
School Location: United States -- Massachusetts
Source: DAI-B 79/02(E), Dissertation Abstracts International
Subjects: Neurosciences
Keywords: Astrocyte, Cortex, Development, Glutamate, Inhibition, NMDA
Publication Number: 10261473
ISBN: 978-0-355-36148-3
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