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Dynamics of membrane tension and synaptic vesicle recycling

Award Number: R01NS122388
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Dynamics of membrane tension and synaptic vesicle recycling - Project Summary Information in the nervous system is relayed mostly at synapses, where neurotransmitter is released with great temporal precision from a presynaptic terminal via the fusion of membrane-bound synaptic vesicles (SVs) with the plasma membrane (PM), in a process called exocytosis. Components of these SVs are subsequently retrieved via endocytosis and recycled for reuse. This grant aims to understand the interplay between SV recycling and membrane tension gradients and associated membrane flows. In neurons and neuroendocrine cells, both exo- and endocytosis are influenced by osmotic forces, suggesting they are influenced by membrane tension, 𝜎𝜎. Conversely, membrane addition to the PM via exocytosis is expected to lower 𝜎𝜎, while endocytosis should restore it. In addition, 𝜎𝜎 has been suggested to be a possible signal for coupling exo- to endocytosis. Despite these key roles, there are no measurements of 𝜎𝜎 in synaptic terminals and how 𝜎𝜎 changes are related to exo-endocytosis is not known, mainly due to technical difficulties. The best method to probe 𝜎𝜎 is to pull a thin membrane tether from the PM using optical tweezers; the tether force reflects 𝜎𝜎. However, most terminals are small and tightly coupled to post-synaptic structures, making tether pulling impractical. We overcome this challenge using fish bipolar neurons which possess giant terminals, in a setup that combines optical tweezers with electrophysiology or photostimulation and with high- resolution fluorescence microscopy. We aim to 1) characterize PM flows at neuronal presynaptic terminals. After stimulation, membrane added at an exocytic site needs to flow (and the associated 𝜎𝜎 perturbation propagate) over the cell surface, then through the tether to produce a change in the measured tether force. We will characterize membrane flows. 2) Determine mechanisms of cell membrane flow regulation by the cytoskeleton. We found that F-actin is a major regulator of PM-cytoskeleton drag, but how it interacts with the PM at terminals and activity-dependent changes in its structure are not understood. We will characterize F- actin rearrangements upon stimulation at the optical and electron microscopy levels. 3) Establish the relationship between tension changes in response to stimulation, membrane flow, and exo-endocytosis coupling. We will confirm that 𝜎𝜎 changes we observed in preliminary experiments are due to exo-endocytosis and map the spatiotemporal relationship between exo- and endocyosis sites as a function of membrane flow to test the idea that exo-endocytosis coupling may depend on membrane flow. 4) Do electromechanical effect matter for exo- or endocytosis? We observed rapid voltage-induced tether force changes consistent with electromechanical effects. The relevance of these effects to exo-endocytosis is not known. We will characterize electromechanical effects and determine whether they may play a role during exo-endocytosis. Overall, these measurements will help generate a model of feedback between membrane trafficking and membrane flows.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $379,030 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/7/2025	NON-COMPETING CONTINUATION	$379,030
														Subtotal = $379,030

Issue Date FY: 2024 ( Subtotal = $408,510 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/24/2024	NON-COMPETING CONTINUATION	$29,480
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/19/2024	NON-COMPETING CONTINUATION	$379,030
														Subtotal = $408,510

Issue Date FY: 2023 ( Subtotal = $421,144 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/17/2023	NON-COMPETING CONTINUATION	$421,144
														Subtotal = $421,144

Issue Date FY: 2022 ( Subtotal = $421,144 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/21/2022	NON-COMPETING CONTINUATION	$421,144
														Subtotal = $421,144

Issue Date FY: 2021 ( Subtotal = $539,944 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/4/2021	NEW	$539,944
														Subtotal = $539,944

Grand Total All Awards = $2,169,772

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Dynamics of membrane tension and synaptic vesicle recycling

Award Number: R01NS122388

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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