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Molecular Mechanisms Underlying PSD-MAGUK/NMDA Receptor Interactions

Award Number: F32MH087010
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2010
PERIOD OF PERFORMANCE END DATE: 03/31/2013

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Molecular Mechanisms Underlying PSD-MAGUK/NMDA Receptor Interactions - DESCRIPTION (provided by applicant): The overall objectives of my proposal are to understand the molecular mechanisms by which glutamate receptors, particularly NMDA receptors (NMDARs), interact with synaptic scaffolding proteins and how these interactions shape synaptic transmission. Specifically, I will study how the postsynaptic density-95-like membrane associated guanylate kinase (PSD-MAGUK) protein family, in particular the protein SAP97, traffic NMDA receptors subunits and change their physiology. PSD-MAGUKs and NMDA receptors play a critical role in basal synaptic transmission and learning and memory, and have been implicated in a wide variety of neurological diseases, ranging from developmental disorders such as autism, schizophrenia, to degenerative diseases such as Alzheimer's. My research goals are outlined in two Specific Aims: Specific Aim 1: SAP97 controls AMPA and NMDA receptor trafficking and synaptic morphology. I hypothesize that SAP97 traffics AMPA and NMDARs to synapses during early development and specifically promotes GluN2A-containing NMDARs. Second, I hypothesize that SAP97-mediated signaling also controls dendrite and synapse morphology in developing neurons. I will manipulate SAP97 protein levels in vivo and use electrophysiology and confocal imaging to measure the role of this protein in synaptic transmission and neuronal anatomy. Specific Aim 2: Molecular differences in PSD-MAGUKs underlie NMDAR kinetics and subunit switching. First, I hypothesize that specific protein binding domains shared by PSD-93, -95, and SAP97 promote synaptic trafficking of GluN2A-containing NMDARs while different motifs in SAP102 promote GluN2B- containing receptors. Second, I hypothesize that PSD-MAGUKs also directly influence NMDAR physiology, with each PSD-MAGUK differentially interacting with NMDARs and shaping synaptic currents. I will design and overexpress chimeric PSD-MAGUK proteins in vivo, in NMDAR subunit conditional knockout mice, and measure the effect on NMDARs using electrophysiology. I will also use a heterologous expression system to measure direct interactions between these proteins. Thus, I will define the protein domains responsible for PSD-MAGUK/NMDAR interactions and how these interactions alter NMDAR physiology. These experiments take a multi-dimensional approach to a vital scientific question, combining cutting edge molecular genetic, physiologocial, and anatomical techniques and will enhance our understanding of fundamental molecular mechanisms of synaptic transmission and learning and memory.


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: 2017 ( Subtotal = -$432 )
2017	2012	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Mental Health National Research Service Awards for Research Training	000	3	5/15/2017	NON-COMPETING CONTINUATION	-$432
														Subtotal = -$432

Issue Date FY: 2012 ( Subtotal = $55,670 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Mental Health National Research Service Awards for Research Training	000	3	3/26/2012	NON-COMPETING CONTINUATION	$55,670
														Subtotal = $55,670

Issue Date FY: 2011 ( Subtotal = $53,042 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Mental Health National Research Service Awards for Research Training	000	2	3/18/2011	NON-COMPETING CONTINUATION	$52,154
2011	2011	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Mental Health National Research Service Awards for Research Training	001	2	5/9/2011	NON-COMPETING CONTINUATION	$888
														Subtotal = $53,042

Issue Date FY: 2010 ( Subtotal = $50,474 )
2010	2010	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Mental Health National Research Service Awards for Research Training	001	1	3/23/2010	NEW	$50,474
2010	2010	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Mental Health National Research Service Awards for Research Training	000	1	3/23/2010	NEW	$0
														Subtotal = $50,474

Grand Total All Awards = $158,754

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Molecular Mechanisms Underlying PSD-MAGUK/NMDA Receptor Interactions

Award Number: F32MH087010

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2010

PERIOD OF PERFORMANCE END DATE: 03/31/2013

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