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Binding of synGAP to PDZ domains of PSD-95 and its role in Intellectual Disability and Autism Spectrum Disorders caused by synGAP haploinsufficiency

Award Number: R01MH115456
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SynGAP Haploinsufficiency is the cause of ~2-5% of sporadic Intellectual Disability (ID) accompanied by autism spectrum disorder (ASD) and/or epilepsy. SynGAP is specifically located postsynaptically and is located in the postsynaptic density (PSD). It has a GTPase activating (GAP) domain that accelerates inactivation of Ras and Rap. However, new evidence, including our own, suggests an additional activity that, when lost, may contribute significantly to the pathology. We have shown that SynGAPa1 binds to all three PDZ domains of the major PSD scaffold protein, PSD-95, and have measured its affinity for each PDZ domain. SynGAPa1 is abundant in the PSD; its a1 isoform could occupy up to 15% of PSD95's PDZ domains in wild type animals and thus compete with binding of other PDZ-domain ligands. We have shown that in synGAP+/- mice (an animal model for synGAP haploinsufficiency), the amount of synGAP in the PSD is reduced and the amounts of other PDZ-domain binding proteins are increased, including TARP-¿2,3,4, and 8, and LRRTM2, both of which are AMPA-type glutamate receptor (AMPAR) chaperone proteins. This change in composition would increase the excitatory/inhibitory balance of synapses onto neurons and contribute to abnormal brain function. Thus, we postulate that reduction of binding of synGAP to PDZ domains of PSD-95 is a major contributor to the ID and ASD observed in SynGAP Haploinsufficiency. We have found that phosphorylation by Ca2+/calmodulin- dependent protein kinase II (CaMKII) decreases the affinity of synGAP for PDZ domains. We postulate that phosphorylation of synGAP is important for reconfiguration of the PSD during early stages of induction of LTP. In Aim One, we will enable quantitative tests of the hypothesis that binding of synGAP to PDZ domains regulates the composition of the PSD by measuring the affinities between PDZ domains of PSD-95 and the carboxyl terminal tails of TARP-¿2,3,4, and 8, LRRTM2, and NR2B. We will express soluble fusion proteins containing the cytosolic carboxyl termini of each protein. To determine affinities for each PDZ domain, we will use Biacore surface plasmon resonance detection of binding to recombinant PDZ domains by the “affinity in solution” method that we perfected for use with synGAP. In Aim Two, we will construct computational models in MCell to simulate equilibrium binding of synGAP and each of these proteins to PSD-95. The models will make use of parameters measured in Aim One. We will construct models of in vitro experiments in order to test their concepts and parameters by comparing simulated results to experimental results. We will then construct spatially realistic models within reconstructed spine geometries to study how the spatial arrangement and high densities of proteins in the spine influence competition among the proteins for binding to PSD-95. In Aim Three, we will use cultured rodent neurons to test the hypothesis that phosphorylation of synGAP drives acute changes in the composition of PSDs in primary neuronal cultures before and after chemical induction of LTP.


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: 2022 ( Subtotal = -$180 )
2022	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	4	9/8/2022	NON-COMPETING CONTINUATION	-$180
														Subtotal = -$180

Issue Date FY: 2021 ( Subtotal = $432,530 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	4	2/1/2021	NON-COMPETING CONTINUATION	$432,530
														Subtotal = $432,530

Issue Date FY: 2020 ( Subtotal = $432,530 )
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	3	2/27/2020	NON-COMPETING CONTINUATION	$432,530
														Subtotal = $432,530

Issue Date FY: 2019 ( Subtotal = $432,530 )
2019	2019	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	2	2/26/2019	NON-COMPETING CONTINUATION	$432,530
														Subtotal = $432,530

Issue Date FY: 2018 ( Subtotal = $449,405 )
2018	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	1	4/25/2018	NEW	$449,405
														Subtotal = $449,405

Grand Total All Awards = $1,746,815

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Binding of synGAP to PDZ domains of PSD-95 and its role in Intellectual Disability and Autism Spectrum Disorders caused by synGAP haploinsufficiency

Award Number: R01MH115456

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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