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The mechanisms and functions of short-term synaptic plasticity

Award Number: R01NS135048
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: 01/15/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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The mechanisms and functions of short-term synaptic plasticity - Project Summary/Abstract Synaptic plasticity, or the ability of neuronal connections to change over time, is essential to the brain’s ability to store and process information. Enduring forms of plasticity such as long-term potentiation and depression contribute to nervous system development, homeostatic tuning, and are thought to underlie learning and memory. In addition, several forms of short-term plasticity modulate synaptic efficacy continuously on rapid times scales ranging from milliseconds to minutes. Our understanding of how these rapid forms of plasticity contribute to the function of the nervous system remains largely theoretical. Identifying the molecular mechanisms for short-term plasticity will enable in vivo manipulations that can remedy this knowledge gap. We recently linked two forms of short-term plasticity to Synaptotagmins (SYTs), a family of molecules that act as crucial regulators of neuronal signaling by conferring Ca2+ sensitivity to the process of synaptic transmission. The high-affinity Ca2+ sensor SYT7 is required for a prominent form of plasticity called facilitation. A closely- related isoform, SYT3, mediates Ca2+-dependent recovery from depression. SYT3 and SYT7 appear to be activated by different patterns of activity, and could thus mediate the majority of activity-dependent plasticity on sub-second time scales. Revealing how these two SYT isoforms perform their functions will provide new insights into the machinery that tightly regulates neurotransmitter release. In this proposal we will use genetic manipulation of both SYTs to answer unsolved questions about the synaptic biophysics of short-term plasticity and its impact on cognitive function. In Aim 1 we will use SYT3, SYT7, and double knockout mice to determine the extent to which these two synaptotagmins determine the properties of short-term plasticity in the cerebellum and hippocampus. In Aim 2 we will explore the molecular interactions that support short-term plasticity using biophysical modeling and activity-dependent synaptic ultrastructure. Finally, in Aim 3 we will use behavioral screening of knockout mice to screen for cognitive deficits that result from altered STP. Our work will help to define the molecular interactions that support the most common forms of short-term plasticity, and lay the foundation to study the contribution of short-term plasticity deficits in neurological disorders.


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: 2026 ( Subtotal = $396,519 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/24/2025	NON-COMPETING CONTINUATION	$396,519
														Subtotal = $396,519

Issue Date FY: 2025 ( Subtotal = $396,519 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/6/2024	NON-COMPETING CONTINUATION	$396,519
														Subtotal = $396,519

Issue Date FY: 2024 ( Subtotal = $479,119 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/2/2024	NEW	$479,119
														Subtotal = $479,119

Grand Total All Awards = $1,272,157

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The mechanisms and functions of short-term synaptic plasticity

Award Number: R01NS135048

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: 01/15/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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