Friday, April 19, 2024 4/19/2024

Regulation of Calcium-permeable AMPA Receptors by AKAP79 Postsynaptic Signaling

Award Number: R01NS040701
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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View Award Abstract

Learning and memory requires multiple forms of synaptic plasticity mediated by mGlu, NMDA, AMPA glutamate receptors (mGluR, NMDAR, AMPAR). These plasticity mechanisms include long-term potentiation (LTP) and long-term depression (LTD), that rapidly increase or decrease synaptic strength of specific inputs, and homeostatic synaptic scaling, which scale-up or -down strength of all inputs. Importantly, alterations in LTP/LTD and homeostatic plasticity are associated with cognitive dysfunction in animal models of nervous system disorders. Until recently, the signaling mechanisms controlling AMPARs during LTP/LTD and homeostatic plasticity were envisioned as distinct. However, LTP/LTD and homeostatic plasticity can both result in synaptic incorporation of high-conductance, Ca2+-permeable AMPA receptors (CP-AMPAR) containing GluA1, but lacking GluA2, subunits that not only impact synaptic strength but also alter plasticity itself - i.e. metaplasticity. Nevertheless, the roles of CP-AMPARs in controlling plasticity in hippocampal neurons are controversial. A major barrier to moving the field forward has been that we do not have an adequate understanding of the signaling mechanisms that control CP-AMPARs. Importantly, recent studies from our laboratory employing knock-in mice demonstrated that the kinase PKA and phosphatase Calcineurin (CaN) anchored to A-kinase anchoring protein (AKAP) 79/150 play opposing roles regulating GluA1 phosphorylation to control both basal and plasticity-regulated CP-AMPAR synaptic incorporation at hippocampal synapses. In particular, we found that AKAP-PKA/CaN positive/negative regulation of CP-AMPAR synaptic incorporation controls LTP/LTD balance and determines whether synapses can undergo homeostatic potentiation. In addition, we found that palmitoylation/depalmitoylation of the AKAP N-terminal targeting domain controls AKAP delivery/removal from dendritic spines in coordination with cellular correlates of LTP/LTD. Furthermore, recent unpublished work indicates that knock-in disruption of AKAP palmitoylation in vivo increases basal CP-AMPAR activity to prevent subsequent LTP. Finally, both published and unpublished data indicate that these CP- AMPAR-mediated changes in plasticity are influenced by developmental age, induction stimulus, and crosstalk with CaMKII and mGlu1 signaling suggesting engagement of metaplasticity. Here we will use the unique knock-in mice we developed to test the overall hypothesis that regulation of AKAP postsynaptic targeting by palmitoylation (aim 1) and CaMKII signaling (aim 2), and interactions between AKAP-PKA/CaN and mGluR signaling (aim 3) control LTP/LTD balance at CA1 synapses through CP-AMPAR-mediated metaplasticity.


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: 2023 ( Subtotal = $432,494 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	3/30/2023	NON-COMPETING CONTINUATION	$432,494
														Subtotal = $432,494

Issue Date FY: 2022 ( Subtotal = $432,494 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	3/17/2022	NON-COMPETING CONTINUATION	$432,494
														Subtotal = $432,494

Issue Date FY: 2021 ( Subtotal = $432,494 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	4/15/2021	NON-COMPETING CONTINUATION	$432,494
														Subtotal = $432,494

Issue Date FY: 2020 ( Subtotal = $432,494 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	18	3/31/2020	NON-COMPETING CONTINUATION	$432,494
2020	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	17	12/16/2019	COMPETING CONTINUATION	$941
2020	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	12/16/2019	SUPPLEMENT FOR EXPANSION	-$941
														Subtotal = $432,494

Issue Date FY: 2019 ( Subtotal = $432,494 )
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	17	4/22/2019	COMPETING CONTINUATION	$432,494
2019	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	4/19/2019	SUPPLEMENT FOR EXPANSION	$0
2019	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	4/19/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $432,494

Issue Date FY: 2018 ( Subtotal = $46,650 )
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	8/10/2018	SUPPLEMENT FOR EXPANSION	$46,650
														Subtotal = $46,650

Issue Date FY: 2017 ( Subtotal = $378,372 )
2017	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	7/14/2017	NON-COMPETING CONTINUATION	$378,372
														Subtotal = $378,372

Issue Date FY: 2016 ( Subtotal = $378,372 )
2016	2016	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	6/24/2016	NON-COMPETING CONTINUATION	$378,372
														Subtotal = $378,372

Issue Date FY: 2015 ( Subtotal = $378,372 )
2015	2015	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	8/3/2015	NON-COMPETING CONTINUATION	$378,372
														Subtotal = $378,372

Issue Date FY: 2014 ( Subtotal = $377,155 )
2014	2014	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	7/17/2014	COMPETING CONTINUATION	$377,155
														Subtotal = $377,155

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2012	UNIVERSITY OF COLORADO DENVER	P.O.BOX 6508	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	5/7/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $390,964 )
2012	2012	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	3/1/2012	NON-COMPETING CONTINUATION	$390,964
														Subtotal = $390,964

Issue Date FY: 2011 ( Subtotal = $397,499 )
2011	2011	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	6/13/2011	NON-COMPETING CONTINUATION	$25,295
2011	2011	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	3/25/2011	NON-COMPETING CONTINUATION	$372,204
														Subtotal = $397,499

Issue Date FY: 2010 ( Subtotal = $397,626 )
2010	2010	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	3/4/2010	NON-COMPETING CONTINUATION	$397,626
														Subtotal = $397,626

Issue Date FY: 2009 ( Subtotal = $391,019 )
2009	2009	UNIVERSITY OF COLORADO DENVER	P.O. BOX 6508	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	7/9/2009	COMPETING CONTINUATION	$391,019
														Subtotal = $391,019

Issue Date FY: 2008 ( Subtotal = $332,935 )
2008	2008	UNIVERSITY OF COLORADO DENVER	P.O.BOX 6508	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	7/18/2008	NON-COMPETING CONTINUATION	$332,935
														Subtotal = $332,935

Issue Date FY: 2007 ( Subtotal = $332,935 )
2007	2007	UNIVERSITY OF COLORADO HEALTH SCIENCES CENTER	P.O.BOX 6508	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	7/18/2007	NON-COMPETING CONTINUATION	$332,935
														Subtotal = $332,935

Issue Date FY: 2006 ( Subtotal = $342,879 )
2006	2006	UNIVERSITY OF COLORADO HEALTH SCIENCES CENTER	P.O.BOX 6508	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	7/27/2006	NON-COMPETING CONTINUATION	$342,879
														Subtotal = $342,879

Issue Date FY: 2005 ( Subtotal = $326,155 )
2005	2005	UNIV OF COLORADO HEALTH SCIENCE CTR	PO BOX 6508 MAIL STOP F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/27/2005	COMPETING CONTINUATION	$326,155
														Subtotal = $326,155

Issue Date FY: 2004 ( Subtotal = $262,529 )
2004	2004	UNIV OF COLORADO HEALTH SCIENCE CTR	PO BOX 6508 MAIL STOP F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/31/2004	NON-COMPETING CONTINUATION	$262,529
														Subtotal = $262,529

Issue Date FY: 2003 ( Subtotal = $262,595 )
2003	2003	UNIV OF COLORADO HEALTH SCIENCE CTR	PO BOX 6508 MAIL STOP F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/28/2003	NON-COMPETING CONTINUATION	$262,595
														Subtotal = $262,595

Issue Date FY: 2002 ( Subtotal = $262,659 )
2002	2002	UNIV OF COLORADO HEALTH SCIENCE CTR	PO BOX 6508 MAIL STOP F428	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/12/2002	NON-COMPETING CONTINUATION	$262,659
														Subtotal = $262,659

Issue Date FY: 2001 ( Subtotal = $321,390 ) (Continued on the next page)
Grand Total All Awards = $7,742,576

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Regulation of Calcium-permeable AMPA Receptors by AKAP79 Postsynaptic Signaling

Award Number: R01NS040701

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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