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Molecular and Cellular Mechanisms Mediating Structural and Functional Active Zone Maturation

Award Number: R01NS117588
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: 02/15/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Molecular and Cellular Mechanisms Mediating Structural and Functional Active Zone Maturation - The current proposal describes experimental approaches to determine how neurons regulate structural and functional maturation of active zones (AZs), a key signaling hub where synaptic communication occurs. Although membrane trafficking mechanisms are highly conserved across cells, additional synapse-specific regulation has evolved to mediate rapid Ca2+- dependent synaptic vesicle (SV) fusion at specialized presynaptic AZs that are precisely aligned to postsynaptic receptors. Multiple evolutionarily conserved proteins are found at AZs, including RIM, RIM binding protein, Syd-1, Liprin-α, ELKS/CAST/Bruchpilot (BRP), Bassoon/Piccolo/Fife and Unc13. Previous studies in our lab demonstrated that the hundreds of AZs formed by a single glutamatergic motoneuron in Drosophila have a heterogeneous distribution of synaptic strength, with neighboring AZs often showing >50-fold differences in the probability of release (Pr) of SVs. We found that AZ maturation drives increased synaptic strength occur over a multi- day developmental period, with newly formed AZs developing as weak Pr sites before maturing into high Pr AZs through the coordinated accumulation of a core set of proteins. In the current application, we will determine how neurons regulate structural and functional maturation of AZs, and how variations in these processes drive synaptic diversity. The mechanisms regulating AZ maturation fall into two broad categories: those that control cell-wide availability of key building blocks to growing AZs (Aim 1) and those that affect capture and retention of new material at individual AZs (Aim 2). We will determine whether specific AZ proteins are produced and transported in excess of their incorporation into growing AZs, or whether their availability at the synaptic terminal is rate-limiting for AZ maturation. In addition, we will characterize the efficiency of material capture at individual AZs throughout the AZ maturation cycle. Finally, we will examine how material availability and capture differ in tonic and phasic motoneurons that innervate the same postsynaptic muscle, but display striking differences in their AZ organization and SV release properties (Aim 3). These studies will provide new insights into how synaptic strength develops across the cohort of AZs of a neuron, as well as how synaptic diversity can be more broadly controlled across neuronal subclasses.


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 = $348,975 )
2025	2025	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/20/2025	NON-COMPETING CONTINUATION	$348,975
														Subtotal = $348,975

Issue Date FY: 2024 ( Subtotal = $376,118 )
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/29/2024	NON-COMPETING CONTINUATION	$348,975
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/9/2024	NON-COMPETING CONTINUATION	$27,143
														Subtotal = $376,118

Issue Date FY: 2023 ( Subtotal = $387,750 )
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/30/2023	NON-COMPETING CONTINUATION	$387,750
														Subtotal = $387,750

Issue Date FY: 2022 ( Subtotal = $387,750 )
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/24/2022	NON-COMPETING CONTINUATION	$38,775
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/31/2022	NON-COMPETING CONTINUATION	$348,975
														Subtotal = $387,750

Issue Date FY: 2021 ( Subtotal = $384,313 )
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/15/2021	NEW	$384,313
														Subtotal = $384,313

Grand Total All Awards = $1,884,906

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Molecular and Cellular Mechanisms Mediating Structural and Functional Active Zone Maturation

Award Number: R01NS117588

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: 02/15/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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