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Microglia-Astrocyte Crosstalk Regulating SynapseRemodeling

Award Number: R01MH113743
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Microglia-Astrocyte Crosstalk Regulating SynapseRemodeling - Project Summary The goal of this proposal is to determine how microglia and astrocytes communicate to remodel synapses. Trillions of synapses form highly precise circuit maps in the brain. These maps are shaped and maintained by sensory experience (vision, touch, etc.), including elimination of less active synapses and f maintenance and strengthening of other synapses. Despite over 50 years of research, the underlying mechanisms by which activity dictates removal of some synapses, but not others, remains an open question. We made the initial discovery that microglia, a resident central nervous system (CNS) macrophage, engulf and eliminate less active synapses in the developing retinogeniculate and barrel cortex circuits. In the last funding cycle, we showed that removal of whiskers on one side of the snout in neonates resulted in microglial engulfment and elimination of thalamocortical (TC) synapses in the corresponding barrel cortex. Unlike the retinogeniculate circuit, this was not regulated by complement. Instead, microglia failed to engulf and eliminate TC synapses in mice deficient in neuronal fractalkine (CX3CL1)-to microglial fractalkine receptor (CX3CR1) signaling. This work established that diverse glial mechanisms regulate activity-dependent synapse remodeling and opened up new questions: Do microglia remodel synapses in the adult brain? With evidence that astrocytes also engulf synapses in other CNS circuits, are astrocytes also involved in barrel cortex synapse remodeling? If so, do they communicate with microglia to regulate this process? Our new preliminary data show that astrocytes do not engulf synapses in response to whisker removal in neonates, but rather they reduce their contact with synapses in a CX3CL1-dependent manner. Also, microglia no longer engulf TC synapses following whisker removal in older animals, concomitant with elevated astrocyte synapse ensheathment. Cell-specific RNAseq following whisker removal further reveals canonical Wnt signaling as a putative mechanism by which microglia signal to astrocytes to regulate synapse ensheathment. We now propose a novel model by which microglia regulate astrocyte ensheathment of synapses in an activity and CX3CL1-CX3CR1-Wnt dependent manner. In turn, microglia gain access to engulf and remove TC synapses. We will now leverage the power of the barrel cortex circuit with cell-specific genetic approaches to: 1) Define the developmental window for CX3CL1-CX3CR1- dependent microglial synapse engulfment and astrocyte synapse ensheathment (Aim 1). 2) Determine if astrocyte ensheathment of synapses impacts microglia-dependent synapse remodeling (Aim 2). 3) Identify how microglia regulate astrocyte ensheathment of synapses (Aim 3). Answers will address how some synapses are eliminated by glia while others are left intact—a key open question in the field with implications for a variety of neurodevelopmental disorders and neurodegenerative diseases with underlying changes in synaptic connectivity.


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 = $459,516 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	9	3/5/2025	NON-COMPETING CONTINUATION	$459,516
														Subtotal = $459,516

Issue Date FY: 2024 ( Subtotal = $540,608 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	002	8	2/15/2024	NON-COMPETING CONTINUATION	$486,547
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	003	8	8/14/2024	NON-COMPETING CONTINUATION	$54,061
2024	2022	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	001	6	2/14/2024	COMPETING CONTINUATION	$716
2024	2021	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	5	2/14/2024	NON-COMPETING CONTINUATION	-$716
														Subtotal = $540,608

Issue Date FY: 2023 ( Subtotal = $579,693 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	7	2/13/2023	NON-COMPETING CONTINUATION	$579,693
														Subtotal = $579,693

Issue Date FY: 2022 ( Subtotal = $619,005 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	6	4/27/2022	COMPETING CONTINUATION	$619,005
														Subtotal = $619,005

Issue Date FY: 2021 ( Subtotal = $418,750 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	5	4/26/2021	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2020 ( Subtotal = $418,750 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	4	4/7/2020	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2019 ( Subtotal = $418,750 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	3	4/29/2019	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2018 ( Subtotal = $405,250 )
2018	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	2	4/24/2018	NON-COMPETING CONTINUATION	$405,250
														Subtotal = $405,250

Issue Date FY: 2017 ( Subtotal = $405,250 )
2017	2017	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Mental Health Research Grants	000	1	7/7/2017	NEW	$405,250
														Subtotal = $405,250

Grand Total All Awards = $4,265,572

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Microglia-Astrocyte Crosstalk Regulating SynapseRemodeling

Award Number: R01MH113743

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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