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Impact of glycine transporter 1 knockout on inhibitory neurotransmission in the lateral superior olive

  • Glycine constitutes the major neurotransmitter at inhibitory synapses of lower brain regions. A rapid removal of glycine from the synaptic cleft and consequent recycling is crucial for synaptic transmission in systems with high effort on temporal precision. This is mainly achieved by glycine translocation via two glycine transporters (GlyTs), namely GlyT1 and GlyT2. At inhibitory synapses, GlyT2 was found to be specifically expressed by neurons, supplying the presynapse with glycine needed for vesicle filling. In contrast, GlyT1 is attributed to astrocytes and primarily mediates the termination of synaptic transmission by glycine removal from the synaptic cleft. Employing patch-clamp recordings from principal neurons of the lateral superior olive (LSO) in acute brainstem slices of GlyT1b/c knockout (KO) mice and wildtype (WT) littermates at postnatal day 20, I analyzed how postsynaptic responses are changed in a GlyT1-depleted environment. During spontaneous vesicle release I found no change of postsynaptic responses, contradicting my initial hypothesis of prolonged decay times. Electrical stimulation of fibers of the medial nucleus of the trapezoid body (MNTB), which are known to form fast, reliable and highly precise synapses with LSO principal neurons, revealed that GlyT1 is involved in proper synaptic function during sustained, high frequent synaptic transmission. Stimulation with 50 Hz led to a stronger decay time and latency prolongation in GlyT1b/c KO, accelerating to 60% longer decay times and 30% longer latencies. Additionally, a more pronounced frequency-dependent depression and fidelity decrease was observed during stimulation with 200 Hz in GlyT1b/c KO, resulting in 67% smaller amplitudes and only 25% of WT fidelity at the end of the challenge. Basic properties like readily releasable pool, release probability, and quantal size (q) were not altered in GlyT1b/c KO, but interestingly q decreased during 50 Hz and 100 Hz challenges to about 84%, which was not observed in WT. I conclude that stronger accumulation of extracellular glycine due to GlyT1 loss leads to prolonged activation of postsynaptic glycine receptors (GlyRs). As a further consequence, activation of presynaptic GlyRs in the vicinity of the synaptic cleft might be enhanced, accompanied by a stronger occurrence of shunting inhibition. Furthermore, I assume a GlyT1-dependent glycine shuttle, which is absent at GlyT1b/c KO synapses. This could result in a diminished glycine supply to GlyT2 located at more distant sites, causing a disturbed replenishment during periods with excess release of glycine. Conclusively, my study reveals a contribution of astrocytes in fast and reliable synaptic transmission at the MNTB-LSO synapse, which in turn is crucial for proper sound source localization.

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Author:Julia Hammerich
Advisor:Eckhard Friauf
Document Type:Doctoral Thesis
Language of publication:English
Publication Date:2019/12/05
Year of Publication:2019
Publishing Institute:Technische Universität Kaiserslautern
Granting Institute:Technische Universität Kaiserslautern
Acceptance Date of the Thesis:2019/11/22
Date of the Publication (Server):2021/05/05
Number of page:VI, 136
Faculties / Organisational entities:Fachbereich Biologie
DDC-Cassification:5 Naturwissenschaften und Mathematik / 500 Naturwissenschaften
Licence (German):Creative Commons 4.0 - Namensnennung, nicht kommerziell, keine Bearbeitung (CC BY-NC-ND 4.0)