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Latrophilin Function in Synapse Formation

Award Number: R01MH126929
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Latrophilin Function in Synapse Formation - Neural circuits are constructed by synapses that connect neurons into vast networks. Although many neural circuits have been characterized, the molecular mechanisms that construct their synaptic architecture remain largely unknown. Synapse formation in neural circuits is thought to be controlled by bi-directional signaling via trans-synaptic adhesion molecules. Strikingly, genetic changes in trans-synaptic adhesion molecules often predispose to neuropsychiatric disorders such as autism and schizophrenia, suggesting that dysfunction of the synaptic architecture of neural circuits contributes to neuropsychiatric disorders, although the nature of the dysfunction is poorly understood. We previously showed that in hippocampal circuits, postsynaptic latrophilins (Lphns) perform a central activity-dependent role in organizing synapses by forming large and diverse trans- synaptic complexes. Surprisingly, Lphn-based complexes include not only presynaptic neurexins, teneurins and FLRTs but also postsynaptic Unc5s, proteins that were previously only known as repulsive axon-guidance cues and not as synapse organizers. Moreover, our previous findings demonstrate that Lphns act as adhesion-GPCRs that organize synapses via two parallel pathways, local cAMP signaling and recruitment of postsynaptic scaffold proteins as phase-separated condensates. However, how Lphn complexes mediate synapse formation in an activity-dependent manner, what the role of Unc5s is in these complexes, and how significant the function of different Lphn-based complexes is for circuit assembly remains largely unknown. To address this knowledge gap, the present application proposes to test the following overall hypotheses in four Specific Aims. Aim 1 will test the hypothesis that Lphns organize synapses by engaging in large trans-synaptic protein complexes that include teneurins, FLRTs, neurexins and Unc5s and that can be reconstituted from purified proteins with associated pre- and postsynaptic specializations; Aim 2 will test the hypothesis that the components of Lphn- based complexes perform distinct essential functions in synapse formation; Aim 3 will test the hypothesis that postsynaptic Lphns and Unc5s utilize diverse signaling pathways to collaboratively organize synapse assembly; and Aim 4 will test the hypothesis that the differential expression and activity-dependent alternative splicing of Lphn-based complex components regulate synapse diversity and circuit plasticity, enabling circuit adaptations critical for learning and memory. Although the Aims of this application are independent of each other, they together form a logical sequence that will advance our understanding of synapse assembly and, given the close genetic association of the pre- and postsynaptic components of Lphn-based complexes with autism and schizophrenia, provide insight into the pathogenesis of neuropsychiatric disorders. In pursuit of these Aims, the application proposes to employ mice as a primary model system and to use an interdisciplinary methodology ranging from reductionist biochemical experiments in order to reconstitute synapses from purified proteins to synaptic function assays in cultured neurons and in vivo to analyses of neural circuits and behavior.


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 = $681,257 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research - Research Projects	001	6	8/3/2026	COMPETING CONTINUATION	$681,257
2026	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	5	7/30/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $681,257

Issue Date FY: 2025 ( Subtotal = $730,761 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	5	5/22/2025	NON-COMPETING CONTINUATION	$730,761
														Subtotal = $730,761

Issue Date FY: 2024 ( Subtotal = $749,601 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	4	4/26/2024	NON-COMPETING CONTINUATION	$749,601
														Subtotal = $749,601

Issue Date FY: 2023 ( Subtotal = $684,688 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	3	4/13/2023	NON-COMPETING CONTINUATION	$684,688
														Subtotal = $684,688

Issue Date FY: 2022 ( Subtotal = $728,567 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	2	4/20/2022	NON-COMPETING CONTINUATION	$36,431
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	2	4/19/2022	NON-COMPETING CONTINUATION	$692,136
														Subtotal = $728,567

Issue Date FY: 2021 ( Subtotal = $730,674 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	1	6/18/2021	NEW	$733,727
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	1	7/9/2021	NEW	-$3,053
														Subtotal = $730,674

Grand Total All Awards = $4,305,548

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Latrophilin Function in Synapse Formation

Award Number: R01MH126929

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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