--- _id: '324' abstract: - lang: eng text: Neuronal networks in the brain consist of two main types of neuron, glutamatergic principal neurons and GABAergic interneurons. Although these interneurons only represent 10–20% of the whole population, they mediate feedback and feedforward inhibition and are involved in the generation of high-frequency network oscillations. A hallmark functional property of GABAergic interneurons, especially of the parvalbumin‑expressing (PV+) subtypes, is the speed of signaling at their output synapse across species and brain regions. Several molecular and subcellular factors may underlie the submillisecond signaling at GABAergic synapses. Such as the selective use of P/Q type Ca2+ channels and the tight coupling between Ca2+ channels and Ca2+ sensors of exocytosis. However, whether the molecular identity of the release sensor contributes to these signaling properties remains unclear. Besides, these interneurons are mainly show depression in response to train of stimuli. How could they keep sufficient release to control the activity of postsynaptic principal neurons during high network activity, is largely elusive. For my Ph.D. work, we firstly examined the Ca2+ sensor of exocytosis at the GABAergic basket cell (BC) to Purkinje cell (PC) synapse in the cerebellum. Immunolabeling suggested that BC terminals selectively expressed synaptotagmin 2 (Syt2), whereas synaptotagmin 1 (Syt1) was enriched in excitatory terminals. Genetic elimination of Syt2 reduced action potential-evoked release to ~10% compared to the wild-type control, identifying Syt2 as the major Ca2+ sensor at BC‑PC synapses. Differential adenovirus-mediated rescue revealed Syt2 triggered release with shorter latency and higher temporal precision, and mediated faster vesicle pool replenishment than Syt1. Furthermore, deletion of Syt2 severely reduced and delayed disynaptic inhibition following parallel fiber stimulation. Thus, the selective use of Syt2 as the release sensor at BC–PC synapse ensures fast feedforward inhibition in cerebellar microcircuits. Additionally, we tested the function of another synaptotagmin member, Syt7, for inhibitory synaptic transmission at the BC–PC synapse. Syt7 is thought to be a Ca2+ sensor that mediates asynchronous transmitter release and facilitation at synapses. However, it is strongly expressed in fast-spiking, PV+ GABAergic interneurons and the output synapses of these neurons produce only minimal asynchronous release and show depression rather than facilitation. How could Syt7, a facilitation sensor, contribute to the depressed inhibitory synaptic transmission needs to be further investigated and understood. Our results indicated that at the BC–PC synapse, Syt7 contributes to asynchronous release, pool replenishment and facilitation. In combination, these three effects ensure efficient transmitter release during high‑frequency activity and guarantee frequency independence of inhibition. Taken together, our results confirmed that Syt2, which has the fastest kinetic properties among all synaptotagmin members, is mainly used by the inhibitory BC‑PC synapse for synaptic transmission, contributing to the speed and temporal precision of transmitter release. Furthermore, we showed that Syt7, another highly expressed synaptotagmin member in the output synapses of cerebellar BCs, is used for ensuring efficient inhibitor synaptic transmission during high activity. alternative_title: - ISTA Thesis article_processing_charge: No author: - first_name: Chong full_name: Chen, Chong id: 3DFD581A-F248-11E8-B48F-1D18A9856A87 last_name: Chen citation: ama: Chen C. Synaptotagmins ensure speed and efficiency of inhibitory neurotransmitter release. 2018. doi:10.15479/AT:ISTA:th_997 apa: Chen, C. (2018). Synaptotagmins ensure speed and efficiency of inhibitory neurotransmitter release. Institute of Science and Technology Austria. https://doi.org/10.15479/AT:ISTA:th_997 chicago: Chen, Chong. “Synaptotagmins Ensure Speed and Efficiency of Inhibitory Neurotransmitter Release.” Institute of Science and Technology Austria, 2018. https://doi.org/10.15479/AT:ISTA:th_997. ieee: C. Chen, “Synaptotagmins ensure speed and efficiency of inhibitory neurotransmitter release,” Institute of Science and Technology Austria, 2018. ista: Chen C. 2018. Synaptotagmins ensure speed and efficiency of inhibitory neurotransmitter release. Institute of Science and Technology Austria. mla: Chen, Chong. Synaptotagmins Ensure Speed and Efficiency of Inhibitory Neurotransmitter Release. Institute of Science and Technology Austria, 2018, doi:10.15479/AT:ISTA:th_997. short: C. Chen, Synaptotagmins Ensure Speed and Efficiency of Inhibitory Neurotransmitter Release, Institute of Science and Technology Austria, 2018. date_created: 2018-12-11T11:45:49Z date_published: 2018-03-01T00:00:00Z date_updated: 2023-09-27T12:26:03Z day: '01' ddc: - '571' degree_awarded: PhD department: - _id: PeJo doi: 10.15479/AT:ISTA:th_997 file: - access_level: open_access checksum: 8e163ae9e927401b9fa7c1b3e6a3631a content_type: application/pdf creator: system date_created: 2018-12-12T10:13:58Z date_updated: 2020-07-14T12:46:04Z file_id: '5046' file_name: IST-2018-997-v1+1_Thesis_chong_a.pdf file_size: 8719458 relation: main_file - access_level: closed checksum: f7d7260029a5fbb5c982db61328ade52 content_type: application/octet-stream creator: dernst date_created: 2019-04-05T09:25:26Z date_updated: 2020-07-14T12:46:04Z file_id: '6221' file_name: 2018_Thesis_chong_source.pages file_size: 47841940 relation: source_file file_date_updated: 2020-07-14T12:46:04Z has_accepted_license: '1' language: - iso: eng month: '03' oa: 1 oa_version: Published Version page: '110' publication_identifier: issn: - 2663-337X publication_status: published publisher: Institute of Science and Technology Austria publist_id: '7541' pubrep_id: '997' related_material: record: - id: '1117' relation: part_of_dissertation status: public - id: '749' relation: part_of_dissertation status: public status: public supervisor: - first_name: Peter M full_name: Jonas, Peter M id: 353C1B58-F248-11E8-B48F-1D18A9856A87 last_name: Jonas orcid: 0000-0001-5001-4804 title: Synaptotagmins ensure speed and efficiency of inhibitory neurotransmitter release tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: dissertation user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 year: '2018' ...