Wednesday, January 15, 2025 1/15/2025

Antidepressants and Intracellular Signaling Linked to BDNF

Award Number: R01MH070727
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary In the previous funding period we investigated the mechanism of rapid antidepressant activity of ketamine, an ionotropic glutamatergic n-methyl-d-aspartate (NMDA) receptor antagonist. We demonstrated that Brain- derived neurotrophic factor (BDNF), and its high affinity receptor TrkB, are required for the rapid antidepressant effects of ketamine as these effects are lost in forebrain specific BDNF knockout mice and conditional forebrain specific TrkB knockout mice. We found the antidepressant effects of ketamine require protein translation, but not transcription, resulting in increases in BDNF protein levels in the hippocampus that are critical for the behavioral effect. Ketamine's blockade of spontaneous NMDA receptor mediated neurotransmission inactivates eukaryotic elongation factor 2 kinase (eEF2K) resulting in dephosphorylation of its only known substrate, eukaryotic elongation factor 2, thereby increasing protein translation of target transcripts, including BDNF. In turn, BDNF is postulated to act via eliciting insertion of 3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptors at the postsynaptic membrane, which results in potentiation of AMPA receptor-mediated CA3-CA1 field excitatory postsynaptic potentials (fEPSPs) by ketamine. While this potentiation is suggested to be a cellular correlate of rapid antidepressant effects, its properties deviate from classical Hebbian forms of plasticity and rather coincide with homeostatic synaptic scaling seen after activity suppression. These data provide the basis for the novel hypothesis that BDNF-TrkB signaling regulates synaptic scaling in vivo that is critical for the rapid antidepressant effects of ketamine. The objective of this renewal is to specifically test the causal and instructive role of BDNF-TrkB signaling in the hippocampus in ketamine-mediated synaptic scaling and rapid antidepressant effects. Collectively, this information will provide novel information on the synaptic locus, as well as key molecules, necessary for ketamine's rapid antidepressant effects.


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: 2024 ( Subtotal = $532,105 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	19	4/23/2024	NON-COMPETING CONTINUATION	$532,105
														Subtotal = $532,105

Issue Date FY: 2023 ( Subtotal = $532,105 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	18	4/11/2023	NON-COMPETING CONTINUATION	$532,105
														Subtotal = $532,105

Issue Date FY: 2022 ( Subtotal = $528,496 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	001	17	6/22/2022	COMPETING CONTINUATION	$532,105
2022	2020	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	16	5/18/2022	NON-COMPETING CONTINUATION	-$2,335
2022	2020	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	002	16	8/30/2022	NON-COMPETING CONTINUATION	-$1,273
														Subtotal = $528,496

Issue Date FY: 2021 ( Subtotal = -$8,388 )
2021	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	16	9/22/2021	NON-COMPETING CONTINUATION	-$8,388
														Subtotal = -$8,388

Issue Date FY: 2020 ( Subtotal = $605,419 )
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	16	5/29/2020	NON-COMPETING CONTINUATION	$605,419
														Subtotal = $605,419

Issue Date FY: 2019 ( Subtotal = $603,743 )
2019	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	005	15	4/22/2019	NON-COMPETING CONTINUATION	$611,699
2019	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	004	14	4/9/2019	SUPPLEMENT FOR EXPANSION	$7,567
2019	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	001	14	2/4/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$539,711
2019	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	003	14	3/29/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$33,529
2019	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	13	2/4/2019	NON-COMPETING CONTINUATION	-$555,234
2019	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	002	12	3/29/2019	NON-COMPETING CONTINUATION	-$33,529
														Subtotal = $603,743

Issue Date FY: 2018 ( Subtotal = $555,234 )
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	001	13	6/4/2018	NON-COMPETING CONTINUATION	$55,524
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	13	3/1/2018	NON-COMPETING CONTINUATION	$499,710
														Subtotal = $555,234

Issue Date FY: 2017 ( Subtotal = $555,234 )
2017	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	001	12	7/25/2017	NON-COMPETING CONTINUATION	$55,522
2017	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	12	4/7/2017	NON-COMPETING CONTINUATION	$499,712
														Subtotal = $555,234

Issue Date FY: 2016 ( Subtotal = $616,138 )
2016	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	001	11	3/22/2016	COMPETING CONTINUATION	$616,138
2016	2014	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	752359022	DALLAS	USA	Mental Health Research Grants	000	10	3/17/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $616,138

Issue Date FY: 2015 ( Subtotal = $0 )
2015	2014	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Mental Health Research Grants	000	10	6/13/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $393,525 )
2014	2014	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	10	4/22/2014	NON-COMPETING CONTINUATION	$393,525
														Subtotal = $393,525

Issue Date FY: 2013 ( Subtotal = $377,784 )
2013	2013	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	9	5/8/2013	NON-COMPETING CONTINUATION	$377,784
														Subtotal = $377,784

Issue Date FY: 2012 ( Subtotal = $393,112 )
2012	2012	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	8	4/14/2012	NON-COMPETING CONTINUATION	$393,112
														Subtotal = $393,112

Issue Date FY: 2011 ( Subtotal = $392,288 )
2011	2011	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	001	7	7/21/2011	NON-COMPETING CONTINUATION	$35,663
2011	2011	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	7	4/22/2011	NON-COMPETING CONTINUATION	$356,625
														Subtotal = $392,288

Issue Date FY: 2010 ( Subtotal = $396,250 )
2010	2010	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	6	8/2/2010	COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2009 ( Subtotal = $236,666 )
2009	2009	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Mental Health Research Grants	000	5	7/3/2009	NON-COMPETING CONTINUATION	$236,666
														Subtotal = $236,666

Issue Date FY: 2008 ( Subtotal = $292,620 )
2008	2008	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Mental Health Research Grants	000	4	7/28/2008	NON-COMPETING CONTINUATION	$292,620
														Subtotal = $292,620

Issue Date FY: 2007 ( Subtotal = $291,272 )
2007	2007	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Mental Health Research Grants	000	3	6/22/2007	NON-COMPETING CONTINUATION	$291,272
														Subtotal = $291,272

Issue Date FY: 2006 ( Subtotal = $298,624 )
2006	2006	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Mental Health Research Grants	001	2	9/21/2006	SUPPLEMENT FOR EXPANSION	$54,890
2006	2006	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Mental Health Research Grants	000	2	6/12/2006	NON-COMPETING CONTINUATION	$243,734
														Subtotal = $298,624

Grand Total All Awards = $7,841,827

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Antidepressants and Intracellular Signaling Linked to BDNF

Award Number: R01MH070727

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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