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Mechanisms and pathogenic role of early corticostriatal dysfunction in Shank3B-/- mice

Award Number: R01MH124695
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Mechanisms and pathogenic role of early corticostriatal dysfunction in Shank3B-/- mice - PROJECT SUMMARY Despite increasing knowledge of the genetic underpinnings of autism risk, the specific pathogenic mechanisms underlying the emergence of motor and cognitive deficits in autism spectrum disorders (ASD) remain unclear. Recent imaging and genetic studies have pointed to corticostriatal dysfunction has a prevalent pathophysiology in ASD. In particular, hypertrophy and abnormal functional connectivity of prefrontal cortex (PFC) and dorsomedial striatum (DMS) have been reported in multiple autistic individuals, providing a potential neuropathological substrate for the repetitive behaviors and social deficits associated with autism. Our laboratory has shown that mice with loss of function deletions in SHANK3 (Shank3B-/-), a highly penetrant monogenic cause of autism, exhibit hyperactivity and abnormal patterns of connectivity in corticostriatal circuits during postnatal development. Behavioral deficits in these animals also emerge during these early developmental periods, suggesting that early corticostriatal dysfunction might be an important pathogenic mechanism in SHANK3 associated disorders. Here we propose to further characterize how striatal circuit development is impaired by loss of Shank3 and identify the specific corticostriatal pathways affected in these conditions (Aim1). In addition, using recently developed conditional transgenic mice that allow cell-specific manipulation of Shank3 expression we will dissect the specific mechanisms leading to corticostriatal connectivity abnormalities (Aim 2). In addition, using new molecular strategies that normalize early excitatory drive in striatal neurons, we will determine the pathogenic role of early striatal circuit dysfunction in the emergence of maladaptive behaviors in Shank3B-/- mice (Aim 3). This work will advance our understanding of the basic mechanisms and developmental rules regulating the maturation of corticostriatal circuits and provide important insights into the pathogenesis of ASD and other neurodevelopmental disorders with early activity imbalances in corticostriatal circuits.


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 = $337,875 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	000	5	11/19/2024	NON-COMPETING CONTINUATION	$337,875
														Subtotal = $337,875

Issue Date FY: 2024 ( Subtotal = $397,500 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	000	4	10/19/2023	NON-COMPETING CONTINUATION	$357,750
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	001	4	6/27/2024	NON-COMPETING CONTINUATION	$39,750
														Subtotal = $397,500

Issue Date FY: 2023 ( Subtotal = $397,500 )
2023	2023	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	000	3	11/4/2022	NON-COMPETING CONTINUATION	$357,750
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	001	3	3/6/2023	NON-COMPETING CONTINUATION	$39,750
														Subtotal = $397,500

Issue Date FY: 2022 ( Subtotal = $393,855 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	001	2	6/21/2022	NON-COMPETING CONTINUATION	$39,386
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Mental Health Research Grants	000	2	10/26/2021	NON-COMPETING CONTINUATION	$354,469
														Subtotal = $393,855

Issue Date FY: 2021 ( Subtotal = $391,250 )
2021	2021	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Mental Health Research Grants	000	1	11/27/2020	NEW	$391,250
														Subtotal = $391,250

Grand Total All Awards = $1,917,980

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Mechanisms and pathogenic role of early corticostriatal dysfunction in Shank3B-/- mice

Award Number: R01MH124695

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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