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Microglia-Neuron Interactions: Roles for Microglial Iba1

Award Number: R21MH124294
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 11/01/2022
PERIOD OF PERFORMANCE END DATE: 10/31/2024

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Microglia-Neuron Interactions: Roles for Microglial Iba1 - ABSTRACT Microglia are brain macrophages derived from yolk-sac progenitors, with classically assigned roles that center on immune surveillance and response to an injury or a disease state. Recent views, however, have moved microglia into the landscape of normal brain function, performing activities such as sculpting and refining of neuronal circuitry in the absence of external stimuli or disease. Thus, understanding the contribution of microglia- neuron interactions in mental health is an area of active interest. Ionized Ca2+-binding adapter molecule 1 (Iba1 a.k.a. AIF1) is a highly conserved protein expressed in microglia. Iba1 has been used widely as a marker of microglia, but its contributions to microglial and brain functions remain largely unknown. In preliminary studies of mice globally deficient for Iba1 function, we have found that this protein is essential for microglial activity, evidenced by reductions in microglial branching and alterations in the total brain expression of several microglial- enriched proteins that have roles in synaptic function and behavior. Furthermore, loss of Iba1 reduces developmental excitatory synaptic strength and synapse numbers but enhances excitation-inhibition ratio involving the pyramidal neurons of CA1 hippocampus. These developmental deficits correlate with a deficit in social interaction in adult Iba1-deficient mice. We hypothesize that microglial Iba1 has important synaptic remodeling functions during postnatal development, which in turn shapes adult behavior. Since, Iba1 is also expressed in CNS-associated macrophages, circulating monocytes and peripheral tissue macrophages, it is unclear whether Iba1 function specifically in microglia contributed to the aforementioned effects in synaptic physiology, gene expression and behavior. To test these ideas, we will take advantage of our unique conditional Iba1 loss-of-function model to manipulate microglial activity. Our two aims address in turn the neurophysiological and behavioral consequences of Iba1 loss from microglial cells during a critical developmental window, and to understand the contributions of Iba1 in the modulation of microglial and synaptic gene expression that underlie an altered synaptic remodeling and behavior. The proposed work will highlight the importance of synaptic developmental functions regulated by a microglia-intrinsic protein and further attempt to showcase the impact of such regulation on behavior. Knowledge gained from this study will advance our understanding of how microglia contribute to the refinement of neuronal circuitry in a developing brain, and thus may provide a rationale for therapeutic targeting of microglia, to advance treatment of neurodevelopmental and neuropsychiatric 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 = -$662 )
2025	2022	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Mental Health Research Grants	000	3	3/25/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$662
														Subtotal = -$662

Issue Date FY: 2023 ( Subtotal = -$11,398 )
2023	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Mental Health Research Grants	002	2	4/5/2023	NON-COMPETING CONTINUATION	-$107,883
2023	2022	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Mental Health Research Grants	001	3	12/23/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$70,202
2023	2022	HOWARD UNIVERSITY	2400 6TH ST NW	WASHINGTON	DC	20059	DISTRICT OF COLUMBIA	USA	Mental Health Research Grants	003	3	4/5/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$107,883
2023	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Mental Health Research Grants	000	2	12/22/2022	NON-COMPETING CONTINUATION	-$81,600
														Subtotal = -$11,398

Issue Date FY: 2022 ( Subtotal = $210,000 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Mental Health Research Grants	000	2	11/1/2021	NON-COMPETING CONTINUATION	$189,000
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Mental Health Research Grants	001	2	6/21/2022	NON-COMPETING CONTINUATION	$21,000
														Subtotal = $210,000

Issue Date FY: 2021 ( Subtotal = $243,989 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Mental Health Research Grants	000	1	12/1/2020	NEW	$243,989
														Subtotal = $243,989

Grand Total All Awards = $441,929

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Microglia-Neuron Interactions: Roles for Microglial Iba1

Award Number: R21MH124294

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 11/01/2022

PERIOD OF PERFORMANCE END DATE: 10/31/2024

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