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How do neurons in the brain decide to refine their synaptic connections in vivo?

Award Number: R01MH111647
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/16/2017
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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How do neurons in the brain decide to refine their synaptic connections in vivo? - Project Summary The formation of functional neural circuits is critical for the proper functioning of the brain. To establish the most efficient synaptic circuits, synaptic connections must be refined by neural activity during development. However, the manner and molecules by which synapse refinement is regulated remain to be elucidated. We have established mouse in vivo systems, in which neural activity can be conditionally controlled, and showed that inactive synaptic connections are eliminated during development, but they are eliminated only when there are other active connections with which to compete. This suggests that active connections send a punishment signal to inactive ones and instruct them to leave by triggering elimination signals within the inactive synapses. Active connections are kept by the presence of stabilization signals. By performing various screens, we have identified that the tyrosine kinases Pyk2 and JAK2 serve as elimination signals of inactive synaptic connections during development. Pyk2 and JAK2 are turned on at inactive synapses in response to punishment signals sent from active synapses to drive inactive synapse elimination. Furthermore, we found that a cell adhesion molecule SIRPa from postsynaptic neurons serves as a stabilization signal for active synapses. Together, we propose that neurons calculate the balance between the elimination signals (Pyk2/JAK2) and the stabilization signals (SIRPa) and determine whether to eliminate or stabilize their synaptic connections. Interestingly, our recent preliminary data suggest that the elimination signals Pyk2 and JAK2 have different roles, with Pyk2 in synapse elimination and JAK2 in axon elimination. Additionally, we found that astrocytic ensheathing of synapses also plays important roles in synapse elimination. To further uncover the molecular mechanisms underlying synapse refinement in vivo, we propose to: Aim 1. Investigate the differential roles of Pyk2 and JAK2 for synapse and axon refinement and how SIRPa regulates their activity. Aim 2: Visualize the elimination signals and their regulation of activity-dependent synapse/axon refinement in vivo. Aim 3: Examine the role(s) of astrocytic sheaths in regulating the elimination signals and synapse refinement. Our project will molecularly delineate how neurons decide to establish functional synaptic connections in the mammalian brain. Many forms of mental illness including autism and schizophrenia are associated with abnormal alterations in synapse refinement. Thus, our studies should also yield novel insights into the etiology and treatment of such 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: 2025 ( Subtotal = $739,143 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	8	12/14/2024	NON-COMPETING CONTINUATION	$739,143
2025	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	002	6	1/14/2025	COMPETING CONTINUATION	$293
2025	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	5	1/14/2025	NON-COMPETING CONTINUATION	-$293
														Subtotal = $739,143

Issue Date FY: 2024 ( Subtotal = $869,580 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	7	11/16/2023	NON-COMPETING CONTINUATION	$782,621
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	7	8/15/2024	NON-COMPETING CONTINUATION	$86,959
														Subtotal = $869,580

Issue Date FY: 2023 ( Subtotal = $869,580 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	6	12/1/2022	COMPETING CONTINUATION	$869,580
2023	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	5	11/30/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $869,580

Issue Date FY: 2021 ( Subtotal = $652,027 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	5	5/20/2021	NON-COMPETING CONTINUATION	$652,027
														Subtotal = $652,027

Issue Date FY: 2020 ( Subtotal = $652,027 )
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	4	5/28/2020	NON-COMPETING CONTINUATION	$652,027
														Subtotal = $652,027

Issue Date FY: 2019 ( Subtotal = $652,027 )
2019	2019	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	3	6/1/2019	NON-COMPETING CONTINUATION	$652,027
														Subtotal = $652,027

Issue Date FY: 2018 ( Subtotal = $652,027 )
2018	2018	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	2	5/15/2018	NON-COMPETING CONTINUATION	$652,027
														Subtotal = $652,027

Issue Date FY: 2017 ( Subtotal = $686,344 )
2017	2017	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	1	8/16/2017	NEW	$686,344
														Subtotal = $686,344

Grand Total All Awards = $5,772,755

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How do neurons in the brain decide to refine their synaptic connections in vivo?

Award Number: R01MH111647

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/16/2017

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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