Glutamate dynamics determine the magnitude of Hebbian synaptic plasticity

Barnes, Jocelyn Ruth (2019) Glutamate dynamics determine the magnitude of Hebbian synaptic plasticity. Masters thesis, Memorial University of Newfoundland.

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Increasing evidence suggests that synaptic NMDA receptors (NMDARs) promote long term potentiation (LTP) while extrasynaptic NMDARs inhibit LTP and promote long term depression (LTD). Glutamate transporters maintain this balance by rapidly clearing glutamate from the extracellular space. In many disease states, transporter dysfunction is thought to underlie LTP deficits. However, the precise relationship between extracellular glutamate dynamics and LTP is unknown. Here, we used an optogenetic sensor of glutamate to monitor glutamate dynamics in real-time during LTP induction. Pharmacologically blocking glutamate transporters slowed clearance and inhibited LTP magnitude in a concentration-dependent manner. Surprisingly, impaired glutamate clearance caused rapid NMDAR desensitization and simultaneous three-fold increases in postsynaptic calcium through L-type voltage gated calcium channels. Overall, our data characterize the relationship between glutamate dynamics and LTP, and identify a novel mechanism underlying LTP impairment due to slow glutamate clearance. These results may be applicable to neurodegenerative diseases associated with impaired synaptic plasticity and glutamate transporter dysfunction.

Item Type: Thesis (Masters)
Item ID: 13822
Additional Information: Includes bibliographical references (pages 88-105).
Keywords: Glutamate dynamics, Synaptic transmission, Long term potentiation, Electrophysiology, High frequency imaging
Department(s): Medicine, Faculty of
Date: May 2019
Date Type: Submission
Digital Object Identifier (DOI):
Medical Subject Heading: Glutamates; Receptors, N-Methyl-D-Aspartate; Amino Acid Transport System X-AG; Depression; Neurodegenerative Diseases; Excitatory Postsynaptic Potentials

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