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Shank3 and the Par polarity complex in neurodevelopmental disorders

Award Number: R21NS125782
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: 09/15/2021
PERIOD OF PERFORMANCE END DATE: 03/14/2025

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Shank3 and the Par polarity complex in neurodevelopmental disorders - Project Summary Autism Spectrum Disorders (ASD) and schizophrenia are two distinct neurodevelopmental disorders with certain shared symptoms. Yet the underlying synaptic mechanisms leading to these distinct and shared behavioral phenotypes remain elusive. Both disorders show a strong genetic component, and recent studies have pointed to a number of shared genes that are mutated in both ASD and schizophrenia. One of the most prominent monogenic genes for both disorders is SHANK3, which encodes a synaptic scaffolding protein. However, the mechanisms by which Shank3 mutations differentially affect synaptic functions are still unclear. A recent study in epithelial cells shows Shank2 interacts with the partitioning-defective (Par) polarity complex, which includes Par3, Par6 and atypical PKC (aPKC). Consistent with this, our preliminary data show that Shank3 interacts with aPKC in vivo, and this interaction is reduced in the Par3 conditional knockout hippocampus. Interestingly, we found that aPKC activation is reduced in Shank3 ASD-associated InsG3680 mutant mouse brains, while an overactivation of aPKC is observed in Shank3 schizophrenia-associated R1117X mutant brains. Thus, we hypothesize that Shank3 targets the Par polarity complex to synapses and regulates its activation. ASD- and schizophrenia-associated Shank3 mutations will result in differential dysregulation of aPKC activation, leading to distinct changes in synaptic plasticity and behavioral defects. In the first aim, we will test the hypothesis that dendritic spine structural plasticity is differentially affected by Shank3 ASD and schizophrenia mutants through dysregulated activation of aPKC. In Aim 2, we will test the hypothesis that dysregulation of aPKC activation in Shank3 mutants leads to altered AMPA receptor (AMPAR) trafficking and nanodomain localization at the spine surface. Our studies will utilize advanced molecular imaging techniques, including τSTED super resolution imaging, FRET and FRAP live cell imaging, combined with two-photon glutamate uncaging-induced dendritic spine structural plasticity. We will also complement these imaging approaches with biochemical analyses in SHANK3 ASD and schizophrenia- associated mutant knockin mouse models. Together, our proposed studies will establish a mechanistic link between Shank3 and the Par polarity complex in regulating synaptic plasticity in neurodevelopmental disorders including ASD and schizophrenia. As Par3 is genetically linked to ASD, schizophrenia, and high cognitive performance, our studies will shed light on the role of a Shank3-Par polarity signaling complex in cognitive defects in neurodevelopmental 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 = $0 )
2025	2021	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/2/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/3/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $412,962 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/11/2021	NEW	$412,962
														Subtotal = $412,962

Grand Total All Awards = $412,962

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Shank3 and the Par polarity complex in neurodevelopmental disorders

Award Number: R21NS125782

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: 09/15/2021

PERIOD OF PERFORMANCE END DATE: 03/14/2025

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