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CHANGE OF GRANTEE INSTITUTION: Autophagy Underlies Synaptic Development and ASDs-Related Social Deficits During Critical Period

Award Number: R21NS118378
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: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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CHANGE OF GRANTEE INSTITUTION: Autophagy Underlies Synaptic Development and ASDs-Related Social Deficits During Critical Period - PROJECT SUMMARY/ABSTRACT During the critical period of brain development, sensory stimuli induce remodeling of cortical synapses by eliminating immature synapses, while strengthening others. Deficits of sensory-dependent synaptic remodeling are thought to underlie the delayed maturation of synapses and imbalance in excitation/inhibition, which underlies hypersensitivity to sensory stimuli and deficits of social behaviors associated with autism and other neuropsychiatric disorders. However, knowledge about how sensory input drives synaptic remodeling is still unmet. Autophagy is a process of programmed degradation and recycling of cellular components via the lysosomal pathway in neurons and other cells and is involved in presynaptic function, synapse elimination and synaptic plasticity in neurons. Our preliminary findings with mouse model indicated that sensory deprivation by trimming whiskers downregulates autophagy in somatosensory neurons, increases the synapse numbers, and leads to sensory and social deficits in adulthood. The objective of this research is to document a role of autophagy in sensory experience-induced remodeling of synapse and its importance on sensory processing and sociability in heathy and diseases. Fragile X syndrome (FXS) is the leading genetic cause of autism, which is associated with hypersensitivity and social deficits. Our preliminary finding that autophagy is decreased in somatosensory cortex of FXS mice suggests that impaired autophagy might be causally related to aberrant synaptic remodeling, as well as the behavioral deficits in adult FXS mice. The underlying hypothesis of this project is that sensory stimuli induce autophagy, and that autophagy is critical to experience-dependent synaptic remodeling during the critical period, which subsequently affect sensory processing and social interactions in adulthood. We further postulate that in FXS mice, while impaired autophagy causes aberrant synaptic remodeling, hypersensitivity and social deficits, activation of autophagy can rescue these disorders. We seek to test this hypothesis in the following: Aim 1. Document a role of autophagy in sensory experience-dependent synapse remodeling, sensory processing and social behaviors. Experiments will: 1) test whether sensory deprivation during the critical period suppress autophagy in somatosensory cortex neurons of wild-type mice; 2) establish that autophagy is critical for sensory-dependent synapse remodeling during the critical period, as well as the correct sensory processing and sociability in adult mice.; and 3) determine that mimicking sensory stimulation with a chemogenetic approach, DREADDS, rescues autophagy, sensory processing and social interactions in sensory-deprived mice. Aim 2. Study the role of autophagy in deficits of sensory processing and social interactions in Fragile X mice. Experiments will: 1) examine whether impaired autophagy is causally related to the deficits of synapse remodeling in somatosensory cortex neurons of Fragile X mice; 2) study the effects of pharmacological autophagy activation on sensory and social deficits in Fragile X mice.


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 = -$4 )
2025	2020	CLEVELAND STATE UNIVERSITY	2121 EUCLID AVE	CLEVELAND	OH	44115	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/11/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$4
														Subtotal = -$4

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	CLEVELAND STATE UNIVERSITY	2121 EUCLID AVE	CLEVELAND	OH	44115	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/27/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2020	CLEVELAND STATE UNIVERSITY	2121 EUCLID AVE	CLEVELAND	OH	44115	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/20/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	CLEVELAND STATE UNIVERSITY	2121 EUCLID AVE	CLEVELAND	OH	44115	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	8/22/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$32,211
2021	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/21/2021	NEW	-$423,302
2021	2020	CLEVELAND STATE UNIVERSITY	2121 EUCLID AVE	CLEVELAND	OH	44115	CUYAHOGA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/21/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$423,302
2021	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	8/22/2021	NEW	-$32,211
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $461,688 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/7/2020	NEW	$461,688
														Subtotal = $461,688

Grand Total All Awards = $461,684

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CHANGE OF GRANTEE INSTITUTION: Autophagy Underlies Synaptic Development and ASDs-Related Social Deficits During Critical Period

Award Number: R21NS118378

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: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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